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For several tissue engineering applications, in particular food products, scaling up culture of mammalian cells is a necessary task. The prevailing method for large scale cell culture is the stirred tank bioreactor where anchor dependent cells are grown on microcarriers suspended in medium. We use a spinner flask system with cells grown on microcarriers to optimize the growth of bovine myoblasts. Freshly isolated primary cells were seeded on microcarriers (Synthemax ® , CellBIND ® and Cytodex ® 1 MCs). In this study, we provide proof of principle that bovine myoblasts can be cultured on microcarriers. No major differences were observed between the three tested microcarriers, except that sparsely populated beads were more common with CellBIND ® and Synthemax ® II beads suggesting a slower initiation of exponential growth than on Cytodex ® . We also provide direct evidence that bovine myoblasts display bead-to-bead transfer. A remarkable pick up of growth was observed by adding new MCs. Bovine myoblasts seem to behave like human mesenchymal stem cells. Thus, our results provide valuable data to further develop and scale-up the production of bovine myoblasts as a prerequisite for efficient and cost-effective development of cultured meat. Applicability to other anchorage dependent cells can extend the importance of these results to cell culture for medical tissue engineering or cell therapy.

Microcarriers are 100- to 300-micron support matrices that permit the growth of adherent cells in bioreactor systems. They have a larger surface area to volume ratio in comparison to single cell monolayers, enabling cost-effective cell production and expansion. Microcarriers are composed of a solid matrix that must be separated from expanded cells during downstream processing stages. The detachment method is chosen on the basis of several factors like cell type, microcarrier surface chemistry, cell confluency and degree of aggregation. The development of microcarriers with a range of physiochemical properties permit controlled cell and protein associations that hold utility for novel therapeutics. In this review, we provide an overview of the recent advances in microcarrier cell culture technology. We also discuss its significance as an ex vivo research tool and the therapeutic potential of newly designed microcarrier systems in vivo.

Agglomeration/microparticulation of anti-asthmatic/anti-inflammatory salmeterol (SX) and fluticasone (FP) in a single vehicle rendered inefficient pulmonary drug redispersion and site targeting. This study designed externally drug coated dual-microcarrier against single microcarrier (SX external coat/FP internal coat) systems and examined their pulmonary drug delivery/targeting profiles. Spray-dried lactose-polyethylene glycol 3000 microcarriers were prepared with magnesium stearate lubricant added where applicable. Both single- and dual-microcarrier systems were subjected to cascade impactor analysis against microcarrier particle size and formulation attributes. In vivo pharmacokinetics/pharmacodynamics profiles were assessed. Small microcarrier (~5 µm) was preferred over larger ones for SX targeting at primary to terminal bronchi. Magnesium stearate promoted drug inhalation via reducing microcarrier aggregation and keeping it small for drug deposition and inhalation. Drug-coated single- and dual-microcarrier systems enabled SX release at upper lung and FP release at lower lung. Drug-coated dual-microcarrier enhanced FP inhaled deposition at lower lung due to the absence of external SX barrier and opportunistic hydrophobic aggregation of SX with magnesium stearate-FP deposited on the same microcarrier. Dual-microcarrier increased pulmonary drug retention with a marginal rise in systemic drug levels and reduced inflammatory lymphocytes/eosinophils/neutrophils infiltration, IL-4/5/9/13 release, mucus production, and bronchoconstriction. Dual-microcarrier is more efficient than single-microcarrier in pulmonary SX/FP delivery.

Microcarrier applications have made great advances in tissue engineering in recent years, which can load cells, drugs, and bioactive factors. These microcarriers can be minimally injected into the defect to help reconstruct a good microenvironment for tissue repair. In order to achieve more ideal performance and face more complex tissue damage, an increasing amount of effort has been focused on microcarriers that can actively respond to external stimuli. These microcarriers have the functions of directional movement, targeted enrichment, material release control, and providing signals conducive to tissue repair. Given the high controllability and designability of magnetic and electroactive microcarriers, the research progress of these microcarriers is highlighted in this review. Their structure, function and applications, potential tissue repair mechanisms, and challenges are discussed. In summary, through the design with clinical translation ability, meaningful and comprehensive experimental characterization, and in-depth study and application of tissue repair mechanisms, stimuli-responsive microcarriers have great potential in tissue repair. [Display omitted] •The current application of magnetic microcarriers and electroactive microcarriers in tissue repair were summarized.•The potential repair mechanisms of magnetic microcarriers and electroactive microcarriers were investigated.•The challenges and development prospects of stimuli-responsive tissue engineering microcarriers were analyzed.

Human mesenchymal stem cell (hMSC)-based therapies are of increasing interest in the field of regenerative medicine. As economic considerations have shown, allogeneic therapy seems to be the most cost-effective method. Standardized procedures based on instrumented single-use bioreactors have been shown to provide billion of cells with consistent product quality and to be superior to traditional expansions in planar cultivation systems. Furthermore, under consideration of the complex nature and requirements of allogeneic hMSC-therapeutics, a new equipment for downstream processing (DSP) was successfully evaluated. This mini-review summarizes both the current state of the hMSC production process and the challenges which have to be taken into account when efficiently producing hMSCs for the clinical scale. Special emphasis is placed on the upstream processing (USP) and DSP operations which cover expansion, harvesting, detachment, separation, washing and concentration steps, and the regulatory demands.

The concept of three-dimensional (3D) cell culture has been proposed to maintain cellular morphology and function as in vivo. Among different approaches for 3D cell culture, microcarrier technology provides a promising tool for cell adhesion, proliferation, and cellular interactions in 3D space mimicking the in vivo microenvironment. In particular, microcarriers based on biopolymers have been widely investigated because of their superior biocompatibility and biodegradability. Moreover, through bottom-up assembly, microcarriers have opened a bright door for fabricating engineered tissues, which is one of the cutting-edge topics in tissue engineering and regeneration medicine. This review takes an in-depth look into the recent advancements of microcarriers based on biopolymers—especially polysaccharides such as chitosan, chitin, cellulose, hyaluronic acid, alginate, and laminarin—for 3D cell culture and the fabrication of engineered tissues based on them. The current limitations and potential strategies were also discussed to shed some light on future directions.

With the accelerated aging tendency, osteoarthritis (OA) has become an intractable global public health challenge. Stem cells and their derivative exosome (Exo) have shown great potential in OA treatment. Research in this area tends to develop functional microcarriers for stem cell and Exo delivery to improve the therapeutic effect. Herein, we develop a novel system of Exo-encapsulated stem cell-recruitment hydrogel microcarriers from liquid nitrogen-assisted microfluidic electrospray for OA treatment. Benefited from the advanced droplet generation capability of microfluidics and mild cryogelation procedure, the resultant particles show uniform size dispersion and excellent biocompatibility. Moreover, acryloylated stem cell recruitment peptides SKPPGTSS are directly crosslinked within the particles by ultraviolet irradiation, thus simplifying the peptide coupling process and preventing its premature release. The SKPPGTSS-modified particles can recruit endogenous stem cells to promote cartilage repair and the released Exo from the particles further enhances the cartilage repair performance through synergistic effects. These features suggest that the proposed hydrogel microcarrier delivery system is a promising candidate for OA treatment.

Recent advancement in cartilage tissue engineering has explored the potential of 3D culture to mimic the in vivo environment of human cartilaginous tissue. Three-dimensional culture using microspheres was described to play a role in driving the differentiation of mesenchymal stem cells to chondrocyte lineage. However, factors such as mechanical agitation on cell chondrogenesis during culture on the microspheres has yet to be elucidated. In this study, we compared the 2D and 3D culture of bone-marrow-derived mesenchymal stem cells (BMSCs) on gelatin microspheres (GMs) in terms of MSC stemness properties, immune-phenotype, multilineage differentiation properties, and proliferation rate. Then, to study the effect of mechanical agitation on chondrogenic differentiation in 3D culture, we cultured BMSCs on GM (BMSCs-GM) in either static or dynamic bioreactor system with two different mediums, i.e., F12: DMEM (1:1) + 10% FBS (FD) and chondrogenic induction medium (CIM). Our results show that BMSCs attached to the GM surface and remained viable in 3D culture. BMSCs-GM proliferated faster and displayed higher stemness properties than BMSCs on a tissue culture plate (BMSCs-TCP). GMs also enhanced the efficiency of in-vitro chondrogenesis of BMSCs, especially in a dynamic culture with higher cell proliferation, RNA expression, and protein expression compared to that in a static culture. To conclude, our results indicate that the 3D culture of BMSCs on gelatin microsphere was superior to 2D culture on a standard tissue culture plate. Furthermore, culturing BMSCs on GM in dynamic culture conditions enhanced their chondrogenic differentiation.

Microsphere technology serves as an efficient and effective platform for cell applications (in vitro cell culture and in vivo cell delivery) due to its mimicry of the 3D native environment, high surface area:volume ratio, and ability to isolate the entrapped cells from the environment. Properties of cell-laden microspheres are determined by the type of application and the cell. While high cell densities are preferable for large-scale therapeutic biomolecule production in vitro, an immunoprotective barrier is most important for allogeneic pancreatic islet transplantation into patients. Furthermore, the biological cells require a suitable microenvironment in terms of its physical and biochemical properties. Here, we discuss applications of cell-laden microspheres and their corresponding design parameters. Polymers for cell-laden microspheres are discussed. Fabrication techniques and key parameters regarding cell-laden microspheres for specific applications are explored. Several uses of cell-laden microspheres (in vitro production of cells and biomolecules, as well as in vivo delivery of cells for tissue regeneration or therapeutic biomolecule secretion on-site) are discussed and summarized.

The gelatin microsphere (GM) provides an attractive option for tissue engineering due to its versatility, as reported by various studies. This review presents the history, characteristics of, and the multiple approaches to, the production of GM, and in particular, the water in oil emulsification technique. Thereafter, the application of GM as a drug delivery system for cartilage diseases is introduced. The review then focusses on the emerging application of GM as a carrier for cells and biologics, and biologics delivery within a cartilage construct. The influence of GM on chondrocytes in terms of promoting chondrocyte proliferation and chondrogenic differentiation is highlighted. Furthermore, GM seeded with cells has been shown to have a high tendency to form aggregates; hence the concept of using GM seeded with cells as the building block for the formation of a complex tissue construct. Despite the advancement in GM research, some issues must still be addressed, particularly the improvement of GM’s ability to home to defect sites. As such, the strategy of intraarticular injection of GM seeded with antibody-coated cells is proposed. By addressing this in future studies, a better-targeted delivery system, that would result in more effective intervention, can be achieved.