Cell-to-cell communication is essential for the organization, coordination, and development of cellular networks and multi-cellular systems. Intercellular communication is mediated by soluble factors (including growth factors, neurotransmitters, and cytokines/chemokines), gap junctions, exosomes and recently described tunneling nanotubes (TNTs). It is unknown whether a combination of these communication mechanisms such as TNTs and gap junctions may be important, but further research is required. TNTs are long cytoplasmic bridges that enable long-range, directed communication between connected cells. The proposed functions of TNTs are diverse and not well understood but have been shown to include the cell-to-cell transfer of vesicles, organelles, electrical stimuli and small molecules. However, the exact role of TNTs and gap junctions for intercellular communication and their impact on disease is still uncertain and thus, the subject of much debate. The combined data from numerous laboratories indicate that some TNT mediate a long-range gap junctional communication to coordinate metabolism and signaling, in relation to infectious, genetic, metabolic, cancer, and age-related diseases. This review aims to describe the current knowledge, challenges and future perspectives to characterize and explore this new intercellular communication system and to design TNT-based therapeutic strategies.

The goal of this study was to determine material effects on cartilage regeneration for scaffolds with the same controlled architecture. The 3D polycaprolactone (PCL), poly (glycerol sebacate) (PGS), and poly (1,8 octanediol-co-citrate) (POC) scaffolds of the same design were physically characterized and tissue regeneration in terms of cell phenotype, cellular proliferation and differentiation, and matrix production were compared to find which material would be most optimal for cartilage regeneration in vitro. POC provided the best support for cartilage regeneration in terms of tissue ingrowth, matrix production, and relative mRNA expressions for chondrocyte differentiation (Col2/Col1). PGS was seen as the least favorable material for cartilage based on its relatively high de-differentiation (Col1), hypertrophic mRNA expression (Col10) and high matrix degradation (MMP13, MMP3) results. PCL still provided microenvironments suitable for cells to be active yet it seemed to cause de-differentiation (Col1) of chondrocytes inside the scaffold while many cells migrated out, growing cartilage outside the scaffold.

Non-invasively monitoring the extent of cell growth, scaffold degradation and tissue development will greatly help tissue engineers to monitor in vivo regenerate tissue function and scaffold degradation. Currently available methods for tissue and scaffold degradation analysis, such as histology and direct mechanical measurements, are not suitable for continuous monitoring of the same sample in vivo as they destroy cells, tissue matrix and scaffolds. In addition, different samples are prepared and measured at varying times, but high tissue growth deviation between specimens and the need for monitoring tissue growth and scaffold degradation at different times requires large sample numbers for statistical analysis. Ultrasound elasticity imaging (UEI) based on phase-sensitive speckle tracking can characterize the internal structural, compositional and functional change of biomaterial scaffolds and engineered tissues at high resolution. In this study, UEI resolution was 250 microm (axial) by 500 microm (lateral) using a commercial ultrasound transducer centered at 5 MHz. This method allows characterization of both globally and locally altered scaffold and engineered tissue elastic properties. Preliminary in vitro and in vivo results with poly(1,8-octanediol-co-citrate) scaffolds support the feasibility of UEI as a non-invasive quantitative monitoring tool for scaffold degradation and engineered tissue formation. This novel non-invasive monitoring tool will provide direct, time-dependent feedback on scaffold degradation and tissue ingrowth for tissue engineers to improve the design process.

Intervertebral disc (IVD) disorders and age-related degeneration are believed to contribute to low back pain. There is significant interest in cell-based strategies for regenerating the nucleus pulposus (NP) region of the disc; however, few scaffolds have been evaluated for their ability to promote or maintain an immature NP cell phenotype. Previous studies have shown that NP cell-laminin interactions promote cell adhesion and biosynthesis, which suggests a laminin-functionalized biomaterial may be useful for promoting or maintaining the NP cell phenotype. Here, a photocrosslinkable poly(ethylene glycol)-laminin 111 (PEG-LM111) hydrogel was developed. PEG-LM111 hydrogel mechanical properties could be tuned within the range of dynamic shear moduli values previously reported for human NP. When primary immature porcine NP cells were seeded onto PEG-LM111 hydrogels of varying stiffnesses, LM111 presenting hydrogels were found to promote cell clustering and increased levels of sGAG production as compared to stiffer LM111 presenting and PEG-only gels. When cells were encapsulated in 3D gels, hydrogel formulation was found to influence NP cell metabolism and expression of proposed NP phenotypic markers, with higher expression of N-cadherin and cytokeratin 8 observed for cells cultured in softer (<1 kPa) PEG-LM111 hydrogels. Overall, these findings suggest that soft, LM111 functionalized hydrogels may promote or maintain the expression of specific markers characteristic of an immature NP cell phenotype.

The findings of the present study suggest that HA/ALG hydrogel is a promising biomaterial for prolonging the retention time of stem cells in VFs and for promotion of VF wound healing.

Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development.

Poly(1,8-octanediol-co-citric acid) (POC) is a synthetic biodegradable elastomer that can be processed into 3D scaffolds for tissue engineering. We investigated the effect of designed porosity on the mechanical properties, permeability and degradation profiles of the POC scaffolds. For mechanical properties, scaffold compressive data was fit to a 1D nonlinear elastic model and solid tensile data was fit to a Neohookean incompressible nonlinear elastic model. Chondrocytes were seeded on scaffolds to assess the biocompatibility of POC. Increased porosity was associated with increased degradation rate, increased permeability, and decreased mechanical stiffness which also became less nonlinear. Scaffold characterization in this paper will provide design guidance for POC scaffolds to meet the mechanical and biological parameters needed for engineering soft tissues such as cartilage.

No abstract