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Novel osteoinductive biomimetic scaffolds stimulate human osteoprogenitor activity--implications for skeletal repair.

The development of new bone formation strategies offers tremendous therapeutic implications in a variety of musculoskeletal diseases. One approach involves harnessing the regenerative capacity of osteoprogenitor bone cells in combination with biomimetic scaffolds generated from appropriate scaffold matrices and osteoinductive factors. The aims of our study were to test the efficacy of two innovative osteoinductive agents: the osteoblast stimulating factor-1 (osf-1), an extracellular matrix-associated protein, and osteoinductive extracts of Saos-2 cells on human osteoprogenitor cells. Saos-2 extracted osteoinductive factors significantly stimulated alkaline phosphatase specific activity in basal and osteogenic conditions. Osf-1 significantly stimulated chemotaxis, total colony formation, alkaline phosphatase-positive colony formation, and alkaline phosphatase specific activity at concentrations as low as 10 pg/ml compared with control cultures. Osteoinductive factors present in Saos-2 cell extracts and osf-1 promoted adhesion, migration, expansion, and differentiation of human osteoprogenitor cells on 3-D scaffolds. The successful generation of 3-D biomimetic structures incorporating osf-1 or osteoinductive factors from Saos-2 cells indicates their potential for de novo bone formation that exploits cell-matrix interactions.

Aged↗

Development and potential of a biomimetic chitosan/type II collagen scaffold for cartilage tissue engineering.

BACKGROUND: Damaged articular cartilage has very limited capacity for spontaneous healing. Tissue engineering provides a new hope for functional cartilage repair. Creation of an appropriate cell carrier is one of the critical steps for successful tissue engineering. With the supposition that a biomimetic construct might promise to generate better effects, we developed a novel composite scaffold and investigated its potential for cartilage tissue engineering. METHODS: Chitosan of 88% deacetylation was prepared via a modified base reaction procedure. A freeze-drying process was employed to fabricate a three-dimensional composite scaffold consisting of chitosan and type II collagen. The scaffold was treated with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. Ultrastructure and tensile strength of the matrix were carried out to assess its physico-chemical properties. After subcutaneous implantation in rabbits, its in vivo biocompatibility and degradability of the scaffold were determined. Its capacity to sustain chondrocyte growth and biosynthesis was evaluated through cell-scaffold co-culture in vitro. RESULTS: The fabricated composite matrix was porous and sponge-like with interconnected pores measuring from 100-250 microm in diameter. After cross-linking, the scaffold displayed enhanced tensile strength. Subcutaneous implantation results indicated the composite matrix was biocompatible and biodegradable. In intro cell-scaffold culture showed the scaffold sustained chondrocyte proliferation and differentiation, and maintained the spheric chondrocytic phenotype. As indicated by immunohistochemical staining, the chondrocytes synthesized type II collagen. CONCLUSIONS: Chitosan and type II collagen can be well blended and developed into a porous 3-D biomimetic matrix. Results of physico-chemical and biological tests suggest the composite matrix satisfies the constraints specified for a tissue-engineered construct and may be used as a chondrocyte carrier for cartilage tissue engineering.

Animals↗

[Experimental study of fast formation of biomimetic apatite coatings on pure titanium surface].

OBJECTIVE: To investigate calcium-phosphate coating on commercial pure titanium substrate using a fast biomimetic procedure. METHODS: The titanium specimens were divided into two groups, group A and group B. The specimens of group A were only treated with the mixture of H2SO4/HCl for 30 min. The specimens of group B were treated with the mixture of H2SO4/HCl for 30 min, immersed into 5 mol/L NaOH solution at 60 degrees C for 24 h, and then heated to 600 degrees C and maintained for 1 h. All specimens were soaked into simulated body fluid-A (SBF) and SBF-B for each day. The surface morphology was observed by field scanning electron microscopy. RESULTS: Dense calcium-phosphate coating deposited on all the titanium surfaces of two groups. The calcium-phosphate coating consisted of spheric structure with a diameter of 1 approximately 3 microm, which was proved to be hydroxycarbonate apatite with the analysis of X-ray diffraction. CONCLUSIONS: Thin hydroxycarbonate apatite coating can deposited on pure titanium using a fast biomimetic procedure.

Apatites↗

Minimally invasive restorative dentistry: a biomimetic approach.

When providing dental treatment for a given patient, the practitioner should use a minimally invasive technique that conserves sound tooth structure as a clinical imperative. Biomimetics is a tenet that guides the author's practice and is generally described as the mimicking of natural life. This can be accomplished in many cases using contemporary composite resins and adhesive dental procedures. Both provide clinical benefits and support the biomimetic philosophy for treatment. This article illustrates a minimally invasive approach for the restoration of carious cervical defects created by poor hygiene exacerbated by the presence of orthodontic brackets.

Adolescent↗

The biomimetics of enamel: a paradigm for organized biomaterials synthesis.

The formation of enamel takes place through a sequence of processes that can be mimicked in inorganic materials chemistry. This chapter describes the generic features of enamel biomineralization in terms of a house-building analogy. Four stages are identified: supramolecular preorganization and spatial patterning; interfacial molecular recognition in inorganic nucleation; vectorial crystallization; and pattern evolution and hierarchy. Each of these concepts can be translated into synthetic approaches to the formation of inorganic materials with organized architectures. An example of applying this biomimetic paradigm is described. Supersaturated water-in-oil microemulsions have been used to synthesize microskeletal calcium phosphates by controlled nucleation and vectorial growth in constrained reaction environments. The results of these preliminary studies suggest that biomimetic concepts could be useful in the fabrication of biomaterial implants with controlled porosity and microstructure.

Amelogenesis↗

Screening and chromatographic assessing of a novel IgG biomimetic ligand.

A novel biomimetic ligand, N-benzyloxycarbonyl-l-tyrosine (N-cbz-l-Tyr), was screened by a combination method of molecular docking and immobilized receptor technique. Then, N-cbz-l-Tyr was immobilized on Sepharose CL-4B to prepare a specific affinity adsorbent for immunoglobulin G (IgG). Scatchard analysis of the binding isotherm for IgG on the adsorbent gave an association constant (K(a)) of 4.91 x 10(6) m(-1) and a theoretical maximum adsorption capacity of 17.3 mg IgG/mL gel. IgG with a purity of 98% was separated from human plasma by this new affinity adsorbent.

Biomimetic Materials↗

Key roles of enzyme positions and membrane surface potentials in the properties of biomimetic membranes.

The coupling of diffusion, reaction, and electrostatic interactions existing in the microenvironment of permeable and charged bi-enzymatic membranes has led to the concept of biomimetic membranes. These membranes permit the active and specific transport of small hydrophilic molecules against their concentration gradients, at constant temperature and pressure. This study shows that such membranes behave in totally different ways, depending both on the relative position of the two enzymes, either within or outside the ionic double layer, and on the membrane surface potentials.

Biomimetic Materials↗

A comparative study of electrochemical deposition and biomimetic deposition of calcium phosphate on porous titanium.

Coating porous titanium with calcium phosphate (Ca-P) is an effective way to enhance titanium's osteoinduction capability. This study investigated the effectiveness of two coating methods: biomimetic deposition (BD) and electrochemical deposition (ED) in aqueous solutions. The titanium surfaces were treated by acidic etching and alkaline before coating. Effects of the pre-coating treatments on Ca-P coating were also investigated. Both deposition methods could produce Ca-P coatings on the inner pore surfaces of the titanium. The BD coatings were thicker and more uniform than were the ED coatings. On the other hand, ED was less sensitive to the condition of the titanium surface, and much faster in the coating deposition. However, ED produces less uniform and thinner coating layers on the inner pore surfaces of the titanium than does BD. The crystal structure of the coating is octacalcium phosphate (OCP) regardless of the deposition method. The morphology of flake-like OCP crystals in the deposition layers is similar for both deposition methods, except that the crystal flakes rupture after ED.

Biocompatible Materials↗

High-valent nonheme iron-oxo species in biomimetic oxidations.

High valent iron-oxo species are often invoked as the key oxidizing agents in the catalytic cycles of oxygen activating nonheme iron enzymes, and three of these intermediates have in fact been characterized. To gain further insight into such species, a number of biomimetic complexes have been designed and investigated as functional models for these enzymes. Progress since 2000 is summarized in this review. Many of the model complexes discussed in this review carry out oxidative transformations of relevance to the enzymatic reactions; however, the participation of a high-valent iron-oxo species (Fe(IV)O or Fe(V)O) can only be inferred. Arguments in support of a metal-based oxidant (rather than an oxygen radical species) usually hinge on the high conversion for the transformation and the nature of the reaction products, as well as the incorporation of label into these products from H(2)(18)O or related species. Within this time period, the first bona fide nonheme Fe(IV)O complexes have been generated and identified spectroscopically, three of which are crystallographically characterized. Taken together, these studies emphasize the important role the supporting polydentate ligand plays in eliciting the desired high-valent iron-oxo chemistry.

Biomimetic Materials↗

Membrane binding and permeation by indolicidin analogs studied by a biomimetic lipid/polydiacetylene vesicle assay.

Membrane binding and relative penetration of indolicidin analogs were studied using lipid/polydiacetylene (PDA) chromatic biomimetic membranes. Colorimetric and fluorescence analyses determined that an indolicidin analog with a proline and tryptophan residue substituted with lysines showed more pronounced bilayer surface interactions, while indolicidin and particularly an indolicidin analog in which all prolines were replaced with alanine residues exhibited deeper insertion into the lipid bilayer. The colorimetric data demonstrated that more pronounced blue-red transitions were observed when the chromatic vesicles incorporated lipopolysaccharide (LPS) within the lipid bilayer, indicating that LPS promoted preferred binding and incorporation of the peptides at the lipid/water interface. The fluorescence quenching experiments further confirmed this outcome. The results indicate that the antibacterial activity of indolicidin most likely requires initial binding to the LPS moieties within bacterial membranes, as well as disruption of the bilayer interface. The degree of hemolysis induced by the analogs, on the other hand, correlated to the extent of penetration into the hydrophobic core of the lipid assembly.

Acetylene↗

Use of a biomimetic chromatographic stationary phase for study of the interactions occurring between inorganic anions and phosphatidylcholine membranes.

A liquid chromatographic method for the study of ion-membrane interactions is reported. A phosphatidylcholine biomimetic stationary phase was established by loading dimyristoylphosphatidylcholine (DMPC) onto a reversed-phase octadecylsilica packed column. This column was then used to study the interaction of some inorganic anions with the stationary phase by UV and conductivity detection. Ten inorganic anions were selected as model ions and were analyzed with the proposed chromatographic system. Anion-DMPC interactions of differing magnitudes were observed for all of the model anions. Perchlorate-DMPC interactions were strongest, followed by thiocyanate-DMPC, iodide-DMPC, chlorate-DMPC, nitrate-DMPC, bromide-DMPC, chloride-DMPC, fluoride-DMPC, and then sulfate-DMPC. Cations in the eluent, especially H(+) ions and divalent cations such as Ca(2+), showed strong effects on anion-DMPC interactions. The chromatographic data suggest that DMPC interacts with both the anions and the cations. Anion-DMPC interactions were dependent on the surface potential of the stationary phase: at low surface potentials anion-DMPC interactions were predominantly solvation dependent in nature whereas at more positive surface potentials anion-DMPC interactions were predominantly electrostatic in nature. Cation-DMPC interactions served to raise the surface potential, causing the anion-DMPC interactions to vary from solvation dependent to electrostatic. The chromatographic data were used to provide quantitative estimates of the enthalpies of the anion-DMPC interactions.

Anions↗

Amine-terminated dendrimers as biomimetic templates for silica nanosphere formation.

In diatoms, silica synthesis occurs by use of complex posttranslationally modified peptides, termed silaffins, and highly complex biological polyamine structures. Silaffin peptides have lysine residues that are modified to long-chain polyamine moieties of N-methyl derivatives of polypropylenimine to drive silica synthesis at slightly acidic pH conditions. Using polypropylenimine (PPI) and PAMAM amine-terminated dendrimers as a biomimetic analogue of the polyamine modifications of silaffins, we have demonstrated the condensation of silica nanospheres. We have shown that the dendrimers react in an amine concentration-dependent fashion yielding silica nanospheres with a distinct size distribution reminiscent of the structures produced from both the modified and nonmodified peptides extracted from diatoms. Additionally, the templates were encapsulated by the growing nanospheres and precipitated from solution in a manner similar to that previously described for the bioactive peptides and polyamines.

Amines↗

Molecular biomimetics: nanotechnology through biology.

Proteins, through their unique and specific interactions with other macromolecules and inorganics, control structures and functions of all biological hard and soft tissues in organisms. Molecular biomimetics is an emerging field in which hybrid technologies are developed by using the tools of molecular biology and nanotechnology. Taking lessons from biology, polypeptides can now be genetically engineered to specifically bind to selected inorganic compounds for applications in nano- and biotechnology. This review discusses combinatorial biological protocols, that is, bacterial cell surface and phage-display technologies, in the selection of short sequences that have affinity to (noble) metals, semiconducting oxides and other technological compounds. These genetically engineered proteins for inorganics (GEPIs) can be used in the assembly of functional nanostructures. Based on the three fundamental principles of molecular recognition, self-assembly and DNA manipulation, we highlight successful uses of GEPI in nanotechnology.

Amino Acid Sequence↗

Decoding mechanoregulation in immunological synapses using biomimetic artificial cells.

Mechanical force-driven signaling has emerged as a key regulator of cell-cell interactions (CCIs), which can enhance immune cell function. However, current biochemical approaches for studying CCIs offer minimal direct control over cellular bulk phenotypes, while synthetic biomaterial systems fail to mimic the dynamic complexity of cells. Here we introduce kpiCells, a biomaterial-based platform that uses a biomimetic membrane-endoplasmic architecture to enable finely tuned phenocopying of cellular states via modular mechanical, chemical and topographical inputs. We demonstrate that kpiCells can engage in physiological CCIs and reproduce critical subcellular features. In T cell systems, kpiCells enable integrated interrogation of afferent mechanosensing pathways and efferent force-exertion pathways, and support measurement of piconewton-scale forces at individual T cell antigen receptors as well as single cell-cell force fingerprints that define activation thresholds. This work establishes kpiCells as a bionic model that enables synthetic material design with the level of functional complexity approaching living cell systems.

Artificial Cells↗

Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis.

Cascade reactions and biomimetic strategies are being increasingly applied to the construction of natural and designed molecules. Such processes, in which ideally a single event triggers the conversion of a starting material to a product which then becomes a substrate for the next reaction until termination leads to a stable final product, are highly desirable not only due to their elegance, but also because of their efficiency and economy in terms of reagent consumption and purification. Often, these multistep, one-pot procedures are accompanied by dramatic increases in molecular complexity and impressive selectivity. The discovery of new molecular diversity from Nature and the demand for more efficient and environmentally benign chemical processes dictates and invites the further development of such synthetic strategies and tactics as we move into a new age of chemical synthesis. Within this article, a number of instructive examples of such synthetic strategies from the principal author's laboratories are discussed.

Biomimetic Materials↗

Biomimetics: its practice and theory.

Biomimetics, a name coined by Otto Schmitt in the 1950s for the transfer of ideas and analogues from biology to technology, has produced some significant and successful devices and concepts in the past 50 years, but is still empirical. We show that TRIZ, the Russian system of problem solving, can be adapted to illuminate and manipulate this process of transfer. Analysis using TRIZ shows that there is only 12% similarity between biology and technology in the principles which solutions to problems illustrate, and while technology solves problems largely by manipulating usage of energy, biology uses information and structure, two factors largely ignored by technology.

Animals↗

A Biomimetic Dual-Targeting Nano-APA-Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy.

Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-β-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.

Humans↗

Highly efficient biomimetic total synthesis and structural verification of bistratamides E and J from Lissoclinum bistratum.

The interesting biological activities of heterocycle-containing cyclic peptide-derived natural products, isolated from marine organisms over the past twenty years, have attracted the interest of many synthetic and natural products chemists. Bistratamides E-J, members of this class of natural products that were isolated very recently from Lissoclinum bistratum, exhibited cytotoxic activity against a human colon tumor (HCT-116) cell line. Here we report the first total syntheses of bistratamides E (1) and J (2) in overall yields of 19 and 34 %, respectively. The thiazole substructures have been synthesized by oxidation of their corresponding thiazoline substructures, which were obtained from cysteine containing peptides using a novel biomimetic approach wherein Val-Cys dipeptide units were converted to thiazolines by a bisphosphonium salt. The final macrocyclization was promoted efficiently using the combination of PyBOP and DMAP. This approach allows the use of readily available Fmoc-protected amino acids to make complex thiazole and oxazoline-containing natural products.

Animals↗