Porous and Nonporous Nerve Conduits: The Effects of a Hydrogel Luminal Filler With and Without a Neurite-Promoting Moiety.

Nerve conduits prefilled with hydrogels are frequently explored in an attempt to promote nerve regeneration. This study examines the interplay in vivo between the porosity of the conduit wall and the level of bioactivity of the hydrogel used to fill the conduit. Nerve regeneration in porous (P) or nonporous (NP) conduits that were filled with either collagen only or collagen enhanced with a covalently attached neurite-promoting peptide mimic of the glycan human natural killer cell antigen-1 (m-HNK) were compared in a 5 mm critical size defect in the mouse femoral nerve repair model.

Self-Assembly and Critical Aggregation Concentration Measurements of ABA Triblock Copolymers with Varying B Block Types: Model Development, Prediction, and Validation.

The dissipative particle dynamics (DPD) simulation technique is a coarse-grained (CG) molecular dynamics-based approach that can effectively capture the hydrodynamics of complex systems while retaining essential information about the structural properties of the molecular species. An advantageous feature of DPD is that it utilizes soft repulsive interactions between the beads, which are CG representation of groups of atoms or molecules. In this study, we used the DPD simulation technique to study the aggregation characteristics of ABA triblock copolymers in aqueous medium.

Multiscale approach for the construction of equilibrated all-atom models of a poly(ethylene glycol)-based hydrogel.

A multiscale modeling approach is presented for the efficient construction of an equilibrated all-atom model of a cross-linked poly(ethylene glycol) (PEG)-based hydrogel using the all-atom polymer consistent force field (PCFF). The final equilibrated all-atom model was built with a systematic simulation toolset consisting of three consecutive parts: (1) building a global cross-linked PEG-chain network at experimentally determined cross-link density using an on-lattice Monte Carlo method based on the bond fluctuation model, (2) recovering the local molecular structure of the network by transitioning from the lattice model to an off-lattice coarse-grained (CG) model parameterized from PCFF, followed by equilibration using high performance molecular dynamics methods, and (3) recovering the atomistic structure of the network by reverse mapping from the equilibrated CG structure, hydrating the structure with explicitly represented water, followed by final equilibration using PCFF parameterization. The developed three-stage modeling approach has application to a wide range of other complex macromolecular hydrogel systems, including the integration of peptide, protein, and/or drug molecules as side-chains within the hydrogel network for the incorporation of bioactivity for tissue engineering, regenerative medicine, and drug delivery applications.

Generation and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds.

Cell replacement therapy with human pluripotent stem cell-derived neurons has the potential to ameliorate neurodegenerative dysfunction and central nervous system injuries, but reprogrammed neurons are dissociated and spatially disorganized during transplantation, rendering poor cell survival, functionality and engraftment in vivo. Here, we present the design of three-dimensional (3D) microtopographic scaffolds, using tunable electrospun microfibrous polymeric substrates that promote in situ stem cell neuronal reprogramming, neural network establishment and support neuronal engraftment into the brain. Scaffold-supported, reprogrammed neuronal networks were successfully grafted into organotypic hippocampal brain slices, showing an ∼ 3.

Design of barrier coatings on kink-resistant peripheral nerve conduits.

Here, we report on the design of braided peripheral nerve conduits with barrier coatings. Braiding of extruded polymer fibers generates nerve conduits with excellent mechanical properties, high flexibility, and significant kink-resistance. However, braiding also results in variable levels of porosity in the conduit wall, which can lead to the infiltration of fibrous tissue into the interior of the conduit.

Modeling the Insertion Mechanics of Flexible Neural Probes Coated with Sacrificial Polymers for Optimizing Probe Design.

Single-unit recording neural probes have significant advantages towards improving signal-to-noise ratio and specificity for signal acquisition in brain-to-computer interface devices. Long-term effectiveness is unfortunately limited by the chronic injury response, which has been linked to the mechanical mismatch between rigid probes and compliant brain tissue. Small, flexible microelectrodes may overcome this limitation, but insertion of these probes without buckling requires supporting elements such as a stiff coating with a biodegradable polymer.

Stepping into the omics era: Opportunities and challenges for biomaterials science and engineering.

Unlabelled: The research paradigm in biomaterials science and engineering is evolving from using low-throughput and iterative experimental designs towards high-throughput experimental designs for materials optimization and the evaluation of materials properties. Computational science plays an important role in this transition. With the emergence of the omics approach in the biomaterials field, referred to as materiomics, high-throughput approaches hold the promise of tackling the complexity of materials and understanding correlations between material properties and their effects on complex biological systems.

Next-generation resorbable polymer scaffolds with surface-precipitated calcium phosphate coatings.

Next-generation synthetic bone graft therapies will most likely be composed of resorbable polymers in combination with bioactive components. In this article, we continue our exploration of E1001(1k), a tyrosine-derived polycarbonate, as an orthopedic implant material. Specifically, we use E1001(1k), which is degradable, nontoxic, and osteoconductive, to fabricate porous bone regeneration scaffolds that were enhanced by two different types of calcium phosphate (CP) coatings: in one case, pure dicalcium phosphate dihydrate was precipitated on the scaffold surface and throughout its porous structure (E1001(1k) + CP).

Local, Controlled Delivery of Local Anesthetics In Vivo from Polymer - Xerogel Composites.

Purpose: Polymer-xerogel composite materials have been introduced to better optimize local anesthetics release kinetics for the pain management. In a previous study, it was shown that by adjusting various compositional and nano-structural properties of both inorganic xerogels and polymers, zero-order release kinetics over 7 days can be achieved in vitro. In this study, in vitro release properties are confirmed in vivo using a model that tests for actual functionality of the released local anesthetics.

Nanoparticles and nanofibers for topical drug delivery.

This review provides the first comprehensive overview of the use of both nanoparticles and nanofibers for topical drug delivery. Researchers have explored the use of nanotechnology, specifically nanoparticles and nanofibers, as drug delivery systems for topical and transdermal applications. This approach employs increased drug concentration in the carrier, in order to increase drug flux into and through the skin.

In vitro methods for screening transdermal formulations.

This article provides a review of the critical in vitro assays utilized in transdermal drug development. In vitro assays such as percutaneous absorption testing and dissolution (drug release) testing are powerful tools for screening potential transdermal compounds and drug quality control, respectively. Several 2D single-cell cultures and 3D human skin equivalents are available for screening compounds with low irritation and sensitization potential.

Constructing Human Skin Equivalents on Porcine Acellular Peritoneum Extracellular Matrix for In Vitro Irritation Testing.

The irritancy of topical products has to be investigated to ensure the safety and compliance. Although several reconstructed human epidermal models have been adopted by the Organization for Economic Cooperation and Development (OECD) to replace in vivo animal irritation testing, these models are based on a single cell type and lack dermal components, which may be insufficient to reflect all of the components of irritation. In our study, we investigated the use of acellular porcine peritoneum extracellular matrix as a substrate to construct full-thickness human skin equivalents (HSEs) for use as irritation screening tool.

The overwhelming use of rat models in nerve regeneration research may compromise designs of nerve guidance conduits for humans.

Rats are not the best model for the evolving complexities we face in designing nerve repair strategies today. The development of effective nerve guidance conduits for nerve regeneration is severely limited by the rat sciatic nerve model as the almost exclusive research model in academia. An immense effort is underway to develop an alternative to autologous nerve grafts for the repair of nerve defects, aiming particularly at larger gap repairs of 5-30 cm or more.

Formulation Strategy for the Delivery of Cyclosporine A: Comparison of Two Polymeric Nanospheres.

A wide range of nanoparticles has been explored for the delivery of highly hydrophobic drugs, but very few publications provide comparative data of the performance of different nanoparticles. To address this need, this publication compares poly(lactic-co-glycolic acid) (PLGA) nanoparticles and nanospheres made from tyrosine-derived tri-block copolymers (termed TyroSpheres) for their respective performance as carriers for cyclosporine A (CSA). Using previously reported data on PLGA, we followed similar experimental protocols to evaluate the in vitro characteristics of TyroSpheres.

Fibronectin Interaction and Enhancement of Growth Factors: Importance for Wound Healing.

This critical review focuses on interactions between cells, fibronectin (FN), and growth factors (GF). Initially, the extracellular matrix (ECM) was thought to serve simply as a reservoir for GFs that would be released as soluble ligands during proteolytic degradation of ECM. This view was rather quickly extended by the observation that ECM could concentrate GFs to the pericellular matrix for more efficient presentation to cell surface receptors.

Molecular Inclusion Complexes of β-Cyclodextrin Derivatives Enhance Aqueous Solubility and Cellular Internalization of Paclitaxel: Preformulation and Assessments.

Drugs with low aqueous solubility and permeability possess substantial challenges in designing effective and safe formulations. Synergistic solubility and permeability enhancement in a simple formulation can increase bioavailability and efficacy of such drugs. To overcome limitations of the clinical formulation of Taxol®, Paclitaxel (PTX) was reformulated with various β-cyclodextrin (CD) derivatives suitable for parenteral administration.

Development and Characterization of Acellular Extracellular Matrix Scaffolds from Porcine Menisci for Use in Cartilage Tissue Engineering.

Given the growing number of arthritis patients and the limitations of current treatments, there is great urgency to explore cartilage substitutes by tissue engineering. In this study, we developed a novel decellularization method for menisci to prepare acellular extracellular matrix (ECM) scaffolds with minimal adverse effects on the ECM. Among all the acid treatments, formic acid treatment removed most of the cellular contents and preserved the highest ECM contents in the decellularized porcine menisci.

Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles.

Bioactive Agarose Carbon-Nanotube Composites are Capable of Manipulating Brain-Implant Interface.

Composite electrodes made of the polysaccharide agarose and carbon nanotube fibers (A-CNE) have shown potential to be applied as tissue-compatible, micro-electronic devices. In the present work, A-CNEs were functionalized using neuro-relevant proteins (laminin and alpha-melanocyte stimulating hormone) and implanted in brain tissue for 1 week (acute response) and 4 weeks (chronic response). Qualitative and quantitative analysis of neuronal and immunological responses revealed significant changes in immunological response to implanted materials depending on the type of biomolecule used.

Synthesis and characterization of Fatty acid/amino Acid self-assemblies.

In this paper, we discuss the synthesis and self-assembling behavior of new copolymers derived from fatty acid/amino acid components, namely dimers of linoleic acid (DLA) and tyrosine derived diphenols containing alkyl ester pendent chains, designated as "R" (DTR). Specific pendent chains were ethyl (E) and hexyl (H). These poly(aliphatic/aromatic-ester-amide)s were further reacted with poly(ethylene glycol) (PEG) and poly(ethylene glycol methyl ether) of different molecular masses, thus resulting in ABA type (hydrophilic-hydrophobic-hydrophilic) triblock copolymers.

A comparison of the performance of mono- and bi-component electrospun conduits in a rat sciatic model.

Synthetic nerve conduits represent a promising strategy to enhance functional recovery in peripheral nerve injury repair. However, the efficiency of synthetic nerve conduits is often compromised by the lack of molecular factors to create an enriched microenvironment for nerve regeneration. Here, we investigate the in vivo response of mono (MC) and bi-component (BC) fibrous conduits obtained by processing via electrospinning poly(ε-caprolactone) (PCL) and gelatin solutions.

Enzymatic surface erosion of high tensile strength polycarbonates based on natural phenols.

Surface erosion has been recognized as a valuable design tool for resorbable biomaterials within the context of drug delivery devices, surface coatings, and when precise control of strength retention is critical. Here we report on high tensile strength, aromatic-aliphatic polycarbonates based on natural phenols, tyrosol (Ty) and homovanillyl alcohol (Hva), that exhibit enzymatic surface erosion by lipase. The Young's moduli of the polymers for dry and fully hydrated samples are 1.

Oligodendrocyte/type-2 astrocyte progenitor cells and glial-restricted precursor cells generate different tumor phenotypes in response to the identical oncogenes.

Despite the great interest in identifying the cell-of-origin for different cancers, little knowledge exists regarding the extent to which the specific origin of a tumor contributes to its properties. To directly examine this question, we expressed identical oncogenes in two types of glial progenitor cells, glial-restricted precursor (GRP) cells and oligodendrocyte/type-2 astrocyte progenitor cells (O-2A/OPCs), and in astrocytes of the mouse CNS (either directly purified or generated from GRP cells). In vitro, expression of identical oncogenes in these cells generated populations differing in expression of antigens thought to identify tumor initiating cells, generation of 3D aggregates when grown as adherent cultures, and sensitivity to the chemotherapeutic agent BCNU.

Tegaserod mimics the neurostimulatory glycan polysialic acid and promotes nervous system repair.

Glycans attached to the cell surface via proteins or lipids or exposed in the extracellular matrix affect many cellular processes, including neuritogenesis, cell survival and migration, as well as synaptic activity and plasticity. These functions make glycans attractive molecules for stimulating repair of the injured nervous system. Yet, glycans are often difficult to synthesize or isolate and have the disadvantage to be unstable in a complex tissue environment.

Investigating the Release of a Hydrophobic Peptide from Matrices of Biodegradable Polymers: An Integrated Method Approach.

The objectives of this work were: (1) to select suitable compositions of tyrosine-derived polycarbonates for controlled delivery of voclosporin, a potent drug candidate to treat ocular diseases, (2) to establish a structure-function relationship between key molecular characteristics of biodegradable polymer matrices and drug release kinetics, and (3) to identify factors contributing in the rate of drug release. For the first time, the experimental study of polymeric drug release was accompanied by a hierarchical sequence of three computational methods. First, suitable polymer compositions used in subsequent neural network modeling were determined by means of response surface methodology (RSM).