Production Of HA Research Articles

Tailoring the microenvironment of MOF-derived Co nanoparticles for efficient higher alcohol production via Fischer-Tropsch synthesis

Alcohols are considered as high value-added products from Fischer–Tropsch synthesis (FTS). Efficient conversion of syngas into higher alcohols (C2+OH, HA) is of great significance but poses grand challenges. Herein, a series of nitrogen-doped carbon confined Co catalysts (Co@NC and K-Co@NC) have been prepared via pyrolysis of different Co-containing ZIF-67 and K addition by ball milling. After K addition for modulation of the microenvironment of Co-containing catalysts, the K-Co@NC catalysts display an enhanced HA selectivity in FTS, with a maximum HA selectivity up to ∼30 % and a space time yield of HA (STYC2+OH) of 58 mg·gcat−1·h−1, reflecting the highest HA productivities for Co-based heterogeneous catalysts under similar FTS conditions. Comprehensive characterization studies reveal that K addition, could not only modulate the surface basicity for suppressing the side reactions, but also act as electron donors for promoting the formation of Co2C species during the FTS process, facilitating CO non-dissociative adsorption and CO insertion for improving alcohol formation in FTS. This work provides a feasible strategy for the design of highly efficient Co-based FTS catalysts for production of HA by utilizing MOF materials as the scaffolds.

Coupled Co-Doped MoS2 and CoS2 as the Dual-Active Site Catalyst for Chemoselective Hydrogenation

Catalytic hydrogenation plays an important role in the industrial production of fine chemicals. Herein, we report a Co-doped MoS2 and CoS2 composite with a coupling interface and successfully apply it for the chemoselective hydrogenation of p-chloronitrobenzene to p-chloroaniline. The target catalyst 0.5CoMoS has ∼100% conversion and ∼100% selectivity. Experiments and theoretical calculations reveal that CoS2 is more favorable for adsorbing and activating H2 and provides active hydrogen (Ha) to Co-doped MoS2 by the coupling interface. By matching the production and consumption rates of Ha, the maximization of the reaction yield was achieved. This work may promote the study of MoS2-based catalysts for chemoselective hydrogenation.

A Review on Current Strategies for Extraction and Purification of Hyaluronic Acid.

Since it is known that hyaluronic acid contributes to soft tissue growth, elasticity, and scar reduction, different strategies of producing HA have been explored in order to satisfy the current demand of HA in pharmaceutical products and formulations. The current interest deals with production via bacterial and yeast fermentation and extraction from animal sources; however, the main challenge is the right extraction technique and strategy since the original sources (e.g., fermentation broth) represent a complex system containing a number of components and solutes, which complicates the achievement of high extraction rates and purity. This review sheds light on the main pathways for the production of HA, advantages, and disadvantages, along with the current efforts in extracting and purifying this high-added-value molecule from different sources. Particular emphasis has been placed on specific case studies attempting production and successful recovery. For such works, full details are given together with their relevant outcomes.

Designing topical hyaluronic acid technology-Size does matter….

IntroductionHyaluronic acid (HA) plays an important role in cellular and extracellular matrix (ECM) homeostasis. Recent studies demonstrate that low molecular weight (MW) HA has pro‐inflammatory characteristics while high MW HA is considered anti‐inflammatory and regenerative. In formulating a topical HA product, the possibility of creating a focused high MW HA technology was posed, combining external surface high MW HA constituents with active agents promoting fibroblast production of high MW in the depths of the dermis.MethodsHuman dermal fibroblasts and keratinocytes were treated with various agents, and RNA sequencing (RNA‐seq) was conducted to identify genes involved in HA synthesis. HA production by fibroblasts was assessed by collecting the culture supernatant, concentrating the protein, and conducting polyacrylamide gel electrophoresis (PAGE). The gel was stained with Stains‐All to identify bands relative to known HA products of different MWs. Subsequently, the supernatants were treated with hyaluronidase to confirm the bands corresponded to HA.ResultsThe RNA‐seq results revealed a variety of agents upregulated HA‐related genes. However, a potent upregulation of HA synthesis gene was observed by hexapeptide‐11 in the keratinocytes and a newly identified proprietary octapeptide in the fibroblasts. PAGE demonstrated not only robust production of HA by octapeptide, but significantly, the HA produced was ~2 Mega Daltons in size. Octapeptide was the most potent stimulator among the tested agents.ConclusionComprehensive in vitro testing identified a group of active agents that stimulated high MW HA production. This novel approach to HA topical application with exclusively high MW HA production should maximize hydration capacity while encouraging regenerative activity within the ECM. Multi‐center trials are underway.

A pericellular hyaluronan matrix is required for the morphological maturation of cortical neurons.

BackgroundHyaluronan (HA) is a major component of the extracellular matrix (ECM) and is involved in many cellular functions. In the adult brain, HA forms macromolecular aggregates around synapses and plays important roles in neural plasticity. In contrast to the well-characterized function of HA in the adult brain, its roles in the developing brain remain largely unknown. MethodsBiochemical and histochemical analyses were performed to analyze the amount, solubility, and localization of HA in the developing mouse brain. By combining in utero labeling, cell isolation, and in vitro cultures, we examined the expression of hyaluronan synthase (HAS) and morphological maturation of cortical neurons. ResultsThe amount of HA increased during perinatal development and decreased in the adult. HA existed as a soluble form in the early stages; however, its solubility markedly decreased during postnatal development. HA localized in cell-sparse regions in the embryonic stages, but was broadly distributed during the postnatal development of the cerebral cortex. Developing cortical neurons expressed both Has2 and Has3, but not Has1, suggesting the autonomous production of HA by neurons themselves. HA formed a pericellular matrix around the cell bodies and neurites of developing cortical neurons, and the inhibition of HA synthesis reduced neurite outgrowth. ConclusionThe formation of the pericellular HA matrix is essential for the proper morphological maturation of developing neurons. General significanceThis study provides new insights into the roles of hyaluronan in the brain.development.

The potential for biorefining of triticale to protein and sugar depends on nitrogen supply and harvest time

Biorefining of green biomasses to produce proteins for feed and food along with fibers/sugars for production of fuels and chemicals constitutes one viable pathway in the transition to a bio-economy. In this respect, maximizing annual biomass output is a key parameter and one potential new concept could be green harvest of cereal crops followed by early establishment of a cover crop. The objective of this study was to evaluate different scenarios for harvesting and biorefining triticale either at maturity or earlier in green growth stages. High-yielding triticale was grown under different regimes of N-application and was harvested at three stages of maturity from green to full maturity. Green biomass was fractionated into a fiber rich pulp and a protein rich juice, from which a protein concentrate was produced. The digestibility and sugar potential of the fiber pulp was evaluated against mature straw by enzymatic hydrolysis after hydrothermal pretreatment. Triticale biomass and protein yield did not increase during the last 5–6 weeks before harvest at maturity in August. On average 21 t ha−1 of dry weight biomass was harvested in early July. Fractionation of protein from the green triticale resulted in the production of 730 kg ha−1 of crude protein in a protein concentrate with an amino acid profile superior to grain protein. The structural carbohydrates in the green biomass and the fiber pulp were less recalcitrant compared to mature straw. The total sugar potential from biorefining of green triticale was under the given conditions up to 5.3 t ha−1.

672 A cosmetic serum formulated with botanical extracts targeting causes of slackened skin improves skin elasticity, firmness, wrinkle severity and facial contours

The appearance of slackened, sagging skin tends to become prevalent in the fourth or fifth decade of life regardless of lifestyle or environmental exposure. The constant effect of gravity over time contributes to the emergence of prominent nasolabial folds and sagging skin along the jawline and neck. As such, a treatment product specifically targeted to lift sagging skin is critical to a skin care regimen. Here, we identified multiple botanical extracts that support 3 specific factors associated with slackened skin in vivo: hyaluronic acid, collagenous fibers, and elastic fibers. The extracts stimulated the production of HA, collagen, laminin or elastin on human dermal fibroblasts. In addition, the extracts inhibited the activity of hyaluronidase, the enzyme that degrades HA in vivo as well as the MMPs that degrade dermal proteins. These extracts were formulated into a cosmetic serum then applied to cultured ex vivo skin. After 7 days, the skin was sectioned and stained for collagen VII, a critical protein that supports the dermal-epidermal junction. Decline of collagen VII correlated with slackened skin. Collagen VII was greatly increased compared to untreated control. In a clinical study, 45 women applied the cosmetic serum to the face twice daily for 12 weeks. Skin firmness and lifting attributes showed statistically significant improvements after 4, 8 and 12 weeks of product use relative to baseline. At least 98% of subjects showed improvements in multiple parameters for lifting along the contours of their face (cheek/jawline.) This serum is an effective treatment to improve the appearance of slackened skin.

Inducing perylenequinone production from a bambusicolous fungus Shiraia sp. S9 through co-culture with a fruiting body-associated bacterium Pseudomonas fulva SB1

BackgroundFungal perylenequinonoid (PQ) pigments from Shiraia fruiting body have been well known as excellent photosensitizers for medical and agricultural uses. The fruiting bodies are colonized by a diverse bacterial community of unknown function. We screened the companion bacteria from the fruiting body of Shiraia sp. S9 and explored the bacterial elicitation on fungal PQ production.ResultsA bacterium Pseudomonas fulva SB1 isolated from the fruiting body was found to stimulate the production of fungal PQs including hypocrellins A, C (HA and HC), and elsinochromes A–C (EA, EB and EC). After 2 days of co-cultures, Shiraia mycelium cultures presented the highest production of HA (325.87 mg/L), about 3.20-fold of that in axenic culture. The co-culture resulted in the induction of fungal conidiation and the formation of more compact fungal pellets. Furthermore, the bacterial treatment up-regulated the expression of polyketide synthase gene (PKS), and activated transporter genes of ATP-binding cassette (ABC) and major facilitator superfamily transporter (MFS) for PQ exudation.ConclusionsWe have established a bacterial co-culture with a host Shiraia fungus to induce PQ biosynthesis. Our results provide a basis for understanding bacterial–fungal interaction in fruiting bodies and a practical co-culture process to enhance PQ production for photodynamic therapy medicine.

Effect of fertilization on water use and yield of hops in mature hop plantation

The effect of decreasing nutrient availability on the ecophysiology and production of hop cones was studied in a plantation of cultivar 'Premiant', in Žatec hop growing region, Czech Republic. The plantation used to be fertilized by 60 t of manure ha(-1) year(-1) until November 2011 when it was discontinued as a part of the measures towards organic farming. Measurements of total evapotranspiration from the plantation using the Bowen ratio energy balance method, transpiration of hop bines by the means of sap flow, soil water and nutrient availability were conducted from 2011 to 2014. The yield of hop cones and the content of alpha acids were monitored in this period too. The concentration of total soil nitrogen (N) dropped from 19.4 mg kg(-1) in March 2012 to 8.2 mg kg(-1) in November 2014. Similarly, the content of N in leaves declined from 4.1% of dry mass in 2012 to 2.5% in 2014. The ratio between total evapotranspiration from the plantation to the potential evapotranspiration (PET) was not affected by the soil nutrient availability and did not vary among the years of study, ranging between average to 91 and 96% of PET. In the contrast to total evapotranspiration and PET, the proportion of hop transpiration on the total evapotranspiration steadily declined from 74 to 46% in 2011 and 2014, respectively. Plant regulation of stomatal conductance changed, bringing along lower stomatal aperture, especially upon the conditions of low vapor pressure deficit. In line with decline in transpiration and stomatal conductance, yield of alpha-acids declined from 204 kg ha(-1) in 2011 to 97 kg ha(-1) in 2014. To sum up, after the stop in fertilizing, total water use of the plantation remained similar as before, but the transpiration and production of alpha acids ha(-1) significantly decreased.

Detection of a new reaction by-product in BDDE cross-linked autoclaved hyaluronic acid hydrogels by LC-MS analysis.

BackgroundHyaluronic acid (HA), a naturally occurring polysaccharide, is used in the production of dermal fillers for esthetic purposes. As it has a few days of half-life in human tissues, HA-based dermal filler is chemically modified to increase its lifetime in the body. The most common modification used in commercial HA-based filler is the cross-linking of HA chains using 1,4-butanediol diglycidyl ether (BDDE) as cross-linking agent. Residual, or unreacted, BDDE is considered nontoxic when it is <2 parts per million (ppm); therefore, the quantification of residual BDDE in the final dermal filler is mandatory to ensure the safety of the patients.Materials and methodsThe present study describes the detection and characterization of one by-product of the cross-linking reaction between BDDE and HA in alkaline conditions by combining both liquid chromatography and mass spectroscopy (LC–MS).ResultsAfter different analyses, it was found that the alkaline conditions and the high temperatures employed to sterilize the HA–BDDE hydrogel promote the formation of this new by-product, a “propene glicol-like” compound. LC–MS analysis confirmed that this by-product have the same monoisotopic mass as that of BDDE, a different retention time (tR), and also a different UV absorbance (λ=200 nm) pattern. Unlike BDDE, it was observed in the LC–MS analysis that this by-product had a higher detection at 200 nm in the same assay conditions.ConclusionThese results suggest that this new compound does not have an epoxide on its structure. The discussion is open to assess the risk of this new by-product found in the production of HA–BDDE hydrogels (HA dermal fillers) for commercial purposes.

Kinetic modeling of hyaluronic acid production in palmyra palm (Borassus flabellifer) based medium by Streptococcus zooepidemicus MTCC 3523

In this study, we evaluated palmyra palm sugar (PJ) formulated medium for HA production using Streptococcus zooepidemicus MTCC 3523. Concurrently, effect of various carbon and nitrogen sources, an analysis of the effect of initial sugar concentration, on HA production were examined. The PJ - soya peptone based medium was found to be the most effective, and resulted in 0.54 ± 0.08 g L-1 of HA titer and specific growth rate of 0.5 ± 0.07 h-1 in shake-flask experiments. Kinetic experiments were performed in a bioreactor, and the initial PJ concentrations were varied from 10 - 50 g L-1. Maximum HA and LA titers (1.22 g L-1 and 20. 2 g L-1) were obtained at 30 g L-1 PJ concentration in bioreactor. Han–Levenspiel substrate inhibition model exhibited best fit for the experimental data. The growth inhibitory PJ concentration was found to be at 90.5 g L-1. Medium based process economic analysis proved PJ and soya peptone based medium as most economical for the production of HA. The present investigation validates the potential of PJ and soya peptone based medium for enhanced economical production of HA. This study will also provide new product dimensions and market avenues, to the marginalized palmyra palm farmers and toddy tapping community, who are unable to secure the right price for their product.

Optimization and effect of dairy industrial waste as media components in the production of hyaluronic acid by Streptococcus thermophilus

ABSTRACTHyaluronic acid (HA) production using a dairy industrial waste is a more cost-efficient strategy than using an expensive synthetic medium. In this study, we investigated the production of HA using Streptococcus thermophilus under shake flask conditions using dairy industrial waste as nutritional supplements, namely whey permeate (WP) and whey protein hydrolysate (WPH). Preliminary screening using Plackett–Burman design exhibited WP, WPH, initial pH, and inoculum size as significant factors influencing HA titer. Response surface methodology design of four factors was formulated at three levels for enhanced production of HA. Shake flask HA fermentation by S. thermophilus was performed under global optimized process conditions and the optimal HA titer (342.93 mg L−1) corroborates with Box–Behnken design prediction. The molecular weight of HA was elucidated as 9.22–9.46 kDa. The ultralow-molecular weight HA reported in this study has a potential role in drug and gene delivery applications.

Analisa Perpindahan Panas dan Pengembunan pada Pengembunan Uap Cair dengan Pengembunan Parsial Bertingkat

Production of charcoal as an alte r native fuel have been growth as the solution of the national problem about decreasing energy source from petroleum. Production of charcoal ha s a useful side product in the form of liquid smoke. The liquid smoke can be used as food preservative in the high grade of liquid smoke and the low grade liquid smoke can be used as wood preservative form termite. The conven t ional process on production liquid smoke it was using redistil l ation the raw liquid smoke f r om direct condensation. This process was consumed lot of energy. Liquid smoke consist of some components which had different boiling point. The aim of this research was to study the influence in using different combination of vertical condensor at the condensation of liquid smoke process f r o the making coconut shell charcoal. This research was done by make some coconut shell charcoal and the smoke which was formed was flown passed some condensors . The result of this research shown that condensation of liquid smoke in the vertical condenser occured a contact between condensation down flow and the vapour. The temperature of the condensation taking point can be adjust by adjusting heat transfer area of the vertical condenser. The tar can be taken at the temperature above 100 0 C. The colour of the liquid smoke was lighter with the lower temperature.

Ovarian cancer-derived ascitic fluids induce a senescence-dependent pro-cancerogenic phenotype in normal peritoneal mesothelial cells.

After the seeding ovarian cancer cells into the peritoneal cavity, ascitic fluid creates a microenvironment in which these cells can survive and disseminate. The exact nature of the interactions between malignant ascitic fluids and peritoneal mesothelial cells (HPMCs) in ovarian cancer progression has so far remained elusive. Here we assessed whether malignant ascitic fluids may promote the senescence of HPMCs and, by doing so, enhance the acquisition of their pro-cancerogenic phenotype. Primary omentum-derived HPMCs, ovarian cancer-derived cell lines (A2780, OVCAR-3, SKOV-3), malignant ascitic fluids and benign ascitic fluids from non-cancerous patients were used in this study. Ovarian cancer cell proliferation, as well as HPMC proliferation and senescence, were determined using flow cytometry and β-galactosidase assays, respectively. Ovarian cancer cell migration was quantified using a Transwell assay. The concentrations of soluble agents in ascitic fluids, conditioned media and cell lysates were measured using DuoSet® Immunoassay Development kits. We found that HPMCs, when exposed to malignant ascitic fluids, exhibited decreased proliferation and increased senescence rates. The malignant ascitic fluids were found to contain elevated levels of HGF, TGF-β1 and GRO-1, of which HGF and GRO-1 were able to induce senescence in HPMCs. We also found that HPMCs subjected to malignant ascitic fluids or exogenously added HGF and GRO-1 stimulated ovarian cancer cell progression, which was manifested by an increased production of HA (adhesion), uPA (proliferation), IL-8 and MCP-1 (migration). Our results indicate that malignant ascitic fluids may contribute to ovarian cancer progression by accelerating the senescence of HPMCs.

Genetic basis for hyper production of hyaluronic acid in natural and engineered microorganisms.

Hyaluronic acid, or HA, is a rigid and linear biopolymer belonging to the class of the glycosaminoglycans, and composed of repeating units of the monosaccharides glucuronic acid and N-acetylglucosamine. HA has multiple important functions in the human body, due to its properties such as bio-compatibility, lubricity and hydrophilicity, it is widely applied in the biomedical, food, health and cosmetic fields. The growing interest in this molecule has motivated the discovery of new ways of obtaining it. Traditionally, HA has been extracted from rooster comb-like animal tissues. However, due to legislation laws HA is now being produced by bacterial fermentation using Streptococcus zooepidemicus, a natural producer of HA, despite it being a pathogenic microorganism. With the expansion of new genetic engineering technologies, the use of organisms that are non-natural producers of HA has also made it possible to obtain such a polymer. Most of the published reviews have focused on HA formulation and its effects on different body tissues, whereas very few of them describe the microbial basis of HA production. Therefore, for the first time this review has compiled the molecular and genetic bases for natural HA production in microorganisms together with the main strategies employed for heterologous production of HA.

Improvement of hypocrellin production by a new fungal source and optimization of cultivation conditions

ABSTRACTHypocrellins is regarded as the new generation of potential photosensitizer in the photodynamic therapy. However, the current production of HA in large quantity is limited, whether extracted from the fruit bodies of Hypcrella bambusae and Shiraia bambusicola, or its fermented mycelia. To break through the bottleneck, we screened over 350 fungal strains from the uncommon moso bamboo (Phyllostachys edulis) seeds, and acquired 14 isolates of Shiraia sp. Hypocrellins were generally extracted from the stroma of S. bambusicola, and however the hypocrellin-producing strains in our study were identified as endophytic fungi, where several of them exhibited significantly high content of hypocrellins. One of them, a newly isolated Shiraia sp. strain ZZZ816 was selected for further research. The hypocrellin production conditions of the strain ZZZ816 under submerged fermentation were optimized by one-factor-at-a-time and orthogonal experiment design. The optimum parameters for the quid fermentation were determined as follows: incubation time (144 h), initial pH (6.0), volume of medium (100/250 mL), rotary speed (130 rpm), mycelial age (60 h) and inoculation level (10%). The optimum culture medium constituents were determined as follows: yeast extract 20g/L, malt sugar 40g/L, FeSO4·H2O 0.5g/L, urea 4.0g/L, MgS04·7H20 0.5g/L and initial pH 5.0. Using submerged fermentation of the optimum production conditions, the maximum content of hypocrellin A from the strain ZZZ816 was 921.6 mg/L, more than the other industrial strains published in the previous reports. The results demonstrated that Shiraia sp. strain ZZZ816 could enhance the hypocrellin production tremendously with optimizing the fermentation progress.

Production of specific-molecular-weight hyaluronan by metabolically engineered Bacillus subtilis 168

Low-molecular-weight hyaluronan (LMW-HA) has attracted much attention because of its many potential applications. Here, we efficiently produced specific LMW-HAs from sucrose in Bacillus subtilis. By coexpressing the identified committed genes (tuaD, gtaB, glmU, glmM, and glmS) and downregulating the glycolytic pathway, HA production was significantly increased from 1.01gL−1 to 3.16gL−1, with a molecular weight range of 1.40×106–1.83×106Da. When leech hyaluronidase was actively expressed after N-terminal engineering (1.62×106UmL−1), the production of HA was substantially increased from 5.96gL−1 to 19.38gL−1. The level of hyaluronidase was rationally regulated with a ribosome-binding site engineering strategy, allowing the production of LMW-HAs with a molecular weight range of 2.20×103–1.42×106Da. Our results confirm that this strategy for the controllable expression of hyaluronidase, together with the optimization of the HA synthetic pathway, effectively produces specific LMW-HAs, and could also be used to produce other LMW polysaccharides.

Influenza virus hemagglutinin as a vaccine antigen produced in bacteria.

Recombinant subunit vaccines based on hemagglutinin proteins produced in bacteria (bacterial HAs) are promising candidates for enhancing the supply of vaccines against influenza, especially for a pandemic. Over 20 years after the failure to obtain the antigen with native HA characteristics in the early 1980's, there are increasing data on successful production of HA proteins in bacteria. The vast majority of bacterial HAs have been based on the HA1 subunit of HA expressed separately or as a component of conjugate vaccines, but those based on the ectodomain and the HA2 subunit have also been reported. The most of HAs have been efficiently expressed as insoluble aggregates called inclusion bodies. Refolded and purified proteins were extensively studied for structure, the ability to bind to sialic acid-containing receptors, antigenicity, immunogenicity and efficacy. The results from these studies contradict the view that glycosylation determines the correct structure of the hemagglutinin, as they proved that bacterial HAs can be valuable vaccine antigens when appropriate folding and purification methods are applied to rationally designed proteins. The best evidence for success in bacterial production of protective HA is that vaccines based on proprietary Toll-like Receptor (VaxInnate) and bacteriophage Qβ-VLPs (Cytos Biotechnology) technologies have been advanced to clinical studies.

Hyaluronan synthesis in cultured tobacco cells (BY‐2) expressing a chlorovirus enzyme: Cytological studies

Extraction of hyaluronan from animals or microbial fermentation has risks including contamination with pathogens and microbial toxins. In this work, tobacco cultured-cells (BY-2) were successfully transformed with a chloroviral hyaluronan synthase (cvHAS) gene to produce hyaluronan. Cytological studies revealed accumulation of HA on the cells, and also in subcellular fractions (protoplasts, miniplasts, vacuoplasts, and vacuoles). Transgenic BY-2 cells harboring a vSPO-cvHAS construct containing the vacuolar targeting signal of sporamin connected to the N-terminus of cvHAS accumulated significant amounts of HA in vacuoles. These results suggested that cvHAS successfully functions on the vacuolar membrane and synthesizes/transports HA into vacuoles. Efficient synthesis of HA using this system provides a new method for practical production of HA.

Microbial production of hyaluronic acid: current state, challenges, and perspectives

Hyaluronic acid (HA) is a natural and linear polymer composed of repeating disaccharide units of β-1, 3-N-acetyl glucosamine and β-1, 4-glucuronic acid with a molecular weight up to 6 million Daltons. With excellent viscoelasticity, high moisture retention capacity, and high biocompatibility, HA finds a wide-range of applications in medicine, cosmetics, and nutraceuticals.Traditionally HA was extracted from rooster combs, and now it is mainly produced via streptococcal fermentation. Recently the production of HA via recombinant systems has received increasing interest due to the avoidance of potential toxins. This work summarizes the research history and current commercial market of HA, and then deeply analyzes the current state of microbial production of HA by Streptococcus zooepidemicus and recombinant systems, and finally discusses the challenges facing microbial HA production and proposes several research outlines to meet the challenges.