Surface-Grafted Biocompatible Polymer Conductors for Stable and Compliant Electrodes for Brain Interfaces.

Durable and conductive interfaces that enable chronic and high-resolution recording of neural activity are essential for understanding and treating neurodegenerative disorders. These chronic implants require long-term stability and small contact areas. Consequently, they are often coated with a blend of conductive polymers and are crosslinked to enhance durability despite the potentially deleterious effect of crosslinking on the mechanical and electrical properties. Here the grafting of the poly(3,4 ethylenedioxythiophene) scaffold, poly(styrenesulfonate)-b-poly(poly(ethylene glycol) methyl ether methacrylate block copolymer brush to gold, in a controlled and tunable manner, by surface-initiated atom-transfer radical polymerization (SI-ATRP) is described. This "block-brush" provides high volumetric capacitance (120 F cm─3), strong adhesion to the metal (4 h ultrasonication), improved surface hydrophilicity, and stability against 10 000 charge-discharge voltage sweeps on a multiarray neural electrode. In addition, the block-brush film showed 33% improved stability against current pulsing. This approach can open numerous avenues for exploring specialized polymer brushes for bioelectronics research and application.

Investigating the Role of Amino Acids in Short Peptides for Hydroxyapatite Binding and Osteogenic Differentiation of Mesenchymal Stem Cells to Aid Bone Regeneration.

Bone defects show a slow rate of osteoconduction and imperfect reconstruction, and the current treatment strategies to treat bone defects suffer from limitations like immunogenicity, lack of cell adhesion, and the absence of osteogenic activity. In this context, bioactive supramolecular peptides and peptide gels offer unique opportunities to develop biomaterials that can play a dominant role in the biomineralization of bone tissues and promote bone formation. In this article, we have demonstrated the potential of six tetrapeptides for specific binding to hydroxyapatite (HAp), a major inorganic component of the bone, and their effect on the growth and osteogenic differentiation of mesenchymal stem cells (MSCs). We adopted a simplistic approach of rationally designing amphiphilic peptides by incorporating amino acids, Ser, pSer, Pro, Hyp, Asp, and Glu, which are present in either collagenous or noncollagenous proteins and render properties like antioxidant, calcification, and mineralization. A total of six tetrapeptides, Trp-Trp-His-Ser (WWHS), Trp-Trp-His-pSer (WWHJ), Trp-Trp-His-Pro (WWHP), Trp-Trp-His-Hyp (WWHO), Trp-Trp-His-Asp (WWHD), and Trp-Trp-His-Glu (WWHE), were synthesized. Four peptides were found to self-assemble into nanofibrillar gels resembling the extracellular matrix (ECM), and the remaining two peptides (WWHJ, WWHP) self-assembled into nanorods. The peptides showed excellent cell adhesion, encapsulation, proliferation, and migration and induced the differentiation of mesenchymal stem cells (MSCs), as evident from the enhanced mineralization, resulting from the upregulation of osteogenic markers, RUNX 2, COL I, OPN, and OCN, alkaline phosphatase (ALP) production, and calcium deposition. The peptides also induced the downregulation of inflammatory markers, TNF-α and iNOS, and the upregulation of the anti-inflammatory marker, IL-10, resulting in M2 macrophage polarization. RANKL and TRAP genes were downregulated in a coculture system of MC3T3-E1 and RAW 264.7 cells, implying that peptides promote osteogenesis and inhibit osteoclastogenesis. The peptide-based biomaterials developed in this work can enhance bone regeneration capacity and show strong potential as scaffolds for bone tissue engineering.

Oxidized pullulan exhibits potent antibacterial activity against S. aureus by disrupting its membrane integrity.

The capability of bacteria to withstand the misuse of antibiotics leads to the generation of multi-drug resistant strains, posing a new challenge to curb wound infections. The biological macromolecules, due to their biocompatibility, biodegradability, and antimicrobial properties, have been explored for a variety of antimicrobial and therapeutic purposes. This work reports that a single-step oxidation of pullulan polymer leads to the formation of oxidized pullulan (o-pullulan), which shows striking antibacterial and antibiofilm activities against the Gram-positive bacteria, Staphylococcus aureus, implicated in wound-related infections. Oxidation of pullulan generates 28 % aldehyde groups (3.462 mmol/g) which exerted 97 % bactericidal activity against S. aureus by targeting cell wall-associated membrane protein SpA (Staphylococcal protein A). The molecular docking, gene silencing, and fluorescence quenching studies revealed a direct binding of o-pullulan with the B and C domains of SpA, which alters the membrane potential and inhibits Ca2+-Mg2+-ATPase pumps. O-pullulan also exhibited scavenging activity against intracellular reactive oxygen species (ROS), and non-immunotoxic activity and was found to be non-toxic to mammalian cells. Thus, o-pullulan shows great promise as an antimicrobial polymer against S. aureus for chronic wound management.

Supramolecular, Nanostructured Assembly of Antioxidant and Antibacterial Peptides Conjugated to Naproxen and Indomethacin for the Selective Inhibition of COX-2, Biofilm, and Inflammation in Chronic Wounds.

Chronic wounds are a major healthcare challenge around the world. The presence of bacterial biofilms, accumulation of reactive oxygen species (ROS), and persistent inflammation have been identified as rate-limiting steps in chronic wound healing. Anti-inflammatory drugs, like naproxen (Npx) and indomethacin (Ind), show poor selectivity for the COX-2 enzyme, which plays a key role in producing inflammatory responses. To address these challenges, we have developed conjugates of Npx and Ind with peptides possessing antibacterial, antibiofilm, and antioxidant properties along with enhanced selectivity for the COX-2 enzyme. We have synthesized and characterized peptide conjugates Npx-YYk, Npx-YYr, Ind-YYk, and Ind-YYr, which were self-assembled into supramolecular gels. As envisaged, the conjugates and gels showed high proteolytic stability and selectivity toward the COX-2 enzyme and potent antibacterial activities (>95% within 12 h) against Gram-positive bacteria Staphylococcus aureus, implicated in wound-related infections, eradication of biofilm (∼80%), and radical scavenging (>90%) properties. Cell culture studies with mouse fibroblast cells (L929) and macrophage-like cells (RAW 264.7) showed that gels were cell proliferative in nature (120% viability), which resulted in faster and more efficient scratch healing. Treatment with gels led to a significant decrease in proinflammatory cytokine (TNF-α and IL-6) expressions and an increase in anti-inflammatory gene (IL-10) expression. The gels developed in this work show great promise as a topical agent for chronic wounds or as a coating for medical devices to prevent medical-device-associated infections.

Self-assembled di- and tripeptide gels for the passive entrapment and pH-responsive, sustained release of an antidiabetic drug, glimepiride.

Diabetes is a global epidemic that poses a severe challenge to public health. The characteristic features of this disease are hyperglycemia and deterioration of the function of pancreatic ß-cells, which leads to oxidative stress and organ damage. Glimepiride is used to treat type II diabetes but is associated with side effects, like lower half-life, faster elimination, and hypoglycemia. Self-assembled peptide gels have drawn attention as a drug delivery depot because of their biocompatibility, diverse design, tunable functionality, and dynamic self-assembly properties. In order to overcome the challenge of oxidative stress and side effects associated with the use of glimepiride, we have developed glimepiride-loaded, self-assembled peptide gels from di- and tripeptides employing amino acids with inherent antioxidant properties. Dipeptides, Fmoc-Tyr-Tyr-NH2 (YY) and Fmoc-Trp-Trp-NH2 (WW), and a tripeptide, Fmoc-Trp-Trp-His-NH2 (WWH), were developed and self-assembled into gels. The gels exhibited excellent viscoelastic properties and self-healing abilities, and the presence of ß-sheet secondary structures. The dipeptide gels provided a sustained drug release but more drug was released at physiological pH (7.4) than acidic pH (5 and 6), whereas the tripeptide gel released more drug at acidic pH. The gels showed free radical scavenging activities of more than 90% and were able to decrease the amount of oxidative stress caused by the ROS in HepG2 cells. They were non-toxic to the cell line tested and HepG2 cells treated with the releasate of tripeptide gels showed enhanced glucose uptake. This work for the first time reports the development of glimepiride-loaded self-assembled peptide gels, which can serve as a dynamic, multidimensional biomaterial to reduce oxidative stress, hypoglycemia, and repetitive dosing of drugs in diabetic patients by controlling glimepiride release.

Bactericidal Characteristics of Bioinspired Nontoxic and Chemically Stable Disordered Silicon Nanopyramids.

Controlling bacterial growth using artificial nanostructures inspired from natural species is of immense importance in biomedical applications. In the present work, a low cost, fast processing, and scalable anisotropic wet etching technique is developed to fabricate the densely packed disordered silicon nanopyramids (SiNPs) with nanosized sharp tips. The bactericidal characteristics of SiNPs are assessed against strains implicated in nosocomial and biomaterial-related infections. Compared to the bare silicon with no antibacterial activities, SiNPs of 1.85 ± 0.28 µm height show 55 and 75% inhibition of Escherichia coli (Gram-negative) and Bacillus subtilis (Gram-positive) bacteria, whereas the silicon nanowires (SiNWs) fabricated using a metal-assisted chemical etching method show 50 and 58% inhibition of E. coli and B. subtilis. The mechanistic studies using a scanning electron microscope and live/dead bacterial cell assay reveal cell rupture and predominance of dead cells on contact with SiNPs and SiNWs, which confirms their bactericidal effects. Chemical stability and cell viability studies demonstrate the biocompatible nature of SiNP and SiNW surfaces. Owing to their capability to kill both Gram-negative and positive bacteria and minimal toxicity to murine fibroblast cells, SiNPs can be used as an antibacterial coating on medical devices to prevent nosocomial and biomaterial-related infections.

Antibacterial PEG-Chitosan Hydrogels for Controlled Antibiotic/Protein Delivery.

Bacterial infections impede the wound-healing process, leading to complications such as chronic wounds and ulcerations. Wound dressings have been used in wound management because of the ease of application, ability to cover irregular wound surfaces, and antibacterial characteristics. For efficient wound management, the dressings must also provide the release of growth factors to aid the tissue regeneration process. Injectable PEG-chitosan hydrogels have been developed for the controlled delivery of ciprofloxacin, an antibiotic, and BSA (decoy for macromolecular growth factors) to prevent infections as well as accelerate the healing process. Hydrogels were fabricated by cross-linking chitosan (0.5% w/v) with bifunctional PEG glyoxylic aldehyde (3, 6, 9, and 12% w/v) and characterized for their cross-linking, surface morphology, viscoelastic, injectability, self-healing, and swelling and degradation characteristics. On loading with ciprofloxacin or BSA, hydrogels provided the sustained release of ciprofloxacin for up to 24 h (≥80%) and that of protein for up to 120 h (≥90%). Ciprofloxacin-loaded hydrogels displayed efficient activities (≥80%) against E. coli and the antibacterial activities were sustained for up to 12 h. The live/dead cell assay showed that the loaded hydrogels are bactericidal, and MTT assay (≥80% cells viable) and cell encapsulation studies showed that hydrogels are nontoxic and cytocompatible toward mammalian cells (NIH-3T3). PEG-chitosan hydrogels may find use as injectable device for the controlled antibiotic and growth factor delivery in antibacterial applications.

Synthesis and Biological Evaluation of 8-Quinolinamines and Their Amino Acid Conjugates as Broad-Spectrum Anti-infectives.

In the search of therapeutic agents for emerging drug-resistant parasites, the synthesis of newer classes of 8-quinolinamines has emerged as a successful chemotherapeutic approach. We report synthesis of 8-quinolinamines bearing 5-alkoxy, 4-methyl, and 2-tert-butyl groups in the quinoline framework and their amino acid conjugates as broad-spectrum anti-infectives. 8-Quinolinamines exhibited potent in vitro antimalarial activity [IC50 = 20-4760 ng/mL (drug-sensitive Plasmodium falciparum D6 strain) and IC50 = 22-4760 ng/mL (drug-resistant P. falciparum W2 strain)]. The most promising analogues have cured all animals at 25 mg/kg/day against drug-sensitive Plasmodium berghei and at 50 mg/kg/day against multidrug-resistant Plasmodium yoelii nigeriensis infections in Swiss mice. The in vitro antileishmanial activities (IC50 = 0.84-5.0 µg/mL and IC90 = 1.95-7.0 µg/mL) comparable to standard drug pentamidine were exhibited by several of the synthesized 8-quinolinamines. At the same time, very promising antifungal activities (Candida albicans-IC50 = 4.93-19.38 µg/mL; Candida glabrata-IC50 = 3.96-19.22 µg/mL; Candida krusei-IC50 = 2.89-18.95 µg/mL; Cryptococcus neoformans-IC50 = 0.67-18.64 µg/mL; and Aspergillus fumigatus-IC50 = 6.0-19.32 µg/mL) and antibacterial activities (Staphylococcus aureus-IC50 = 1.33-18.9 µg/mL; methicillin-resistant S. aureus-IC50 = 1.38-15.34 µg/mL; and Mycobacterium intracellulare-IC50 = 3.12-20 µg/mL) were also observed. None of the 8-quinolinamines exhibited cytotoxicity and therefore are a promising structural class of compounds as antiparasitic and antimicrobials.