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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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2018 Impact Factor: 1.847

Front. Med.    2022, Vol. 16 Issue (3) : 358-377    https://doi.org/10.1007/s11684-021-0903-0
REVIEW
Microorganism-derived biological macromolecules for tissue engineering
Naser Amini1,2, Peiman Brouki Milan1,2,3(), Vahid Hosseinpour Sarmadi1,2, Bahareh Derakhshanmehr2, Ahmad Hivechi1,4, Fateme Khodaei5, Masoud Hamidi6, Sara Ashraf7, Ghazaleh Larijani7, Alireza Rezapour8,9()
1. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1591639675, Iran
2. Institutes of Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
3. Department of Tissue Engineering and Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
4. Department of Pharmaceutics, University of Minnesota, MN 55455, USA
5. Burn Research Center, Department of Plastic and Reconstructive Surgery, Iran University of Medical Sciences, Tehran 1591639675, Iran
6. Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht 4477166595, Iran
7. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran
8. Cellular and Molecular Research Centre, Qom University of Medical Sciences, Qom 3715835155, Iran
9. Department of Tissue Engineering and Regenerative Medicine, School of Medicine, Qom University of Medical Sciences, Qom 3715835155, Iran
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Abstract

According to literature, certain microorganism productions mediate biological effects. However, their beneficial characteristics remain unclear. Nowadays, scientists concentrate on obtaining natural materials from live creatures as new sources to produce innovative smart biomaterials for increasing tissue reconstruction in tissue engineering and regenerative medicine. The present review aims to introduce microorganism-derived biological macromolecules, such as pullulan, alginate, dextran, curdlan, and hyaluronic acid, and their available sources for tissue engineering. Growing evidence indicates that these materials can be used as biological material in scaffolds to enhance regeneration in damaged tissues and contribute to cosmetic and dermatological applications. These natural-based materials are attractive in pharmaceutical, regenerative medicine, and biomedical applications. This study provides a detailed overview of natural-based biomaterials, their chemical and physical properties, and new directions for future research and therapeutic applications.

Keywords biological macromolecules      regenerative medicine      tissue engineering      exopolysaccharide      carbohydrate     
Corresponding Author(s): Peiman Brouki Milan,Alireza Rezapour   
Just Accepted Date: 26 April 2022   Issue Date: 18 July 2022
 Cite this article:   
Naser Amini,Peiman Brouki Milan,Vahid Hosseinpour Sarmadi, et al. Microorganism-derived biological macromolecules for tissue engineering[J]. Front. Med., 2022, 16(3): 358-377.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0903-0
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/358
Fig.1  Three different pathways of EPS biosynthesis. (1) Wzx/Wzy-dependent pathway, (2) ABC transporter–dependent pathway, (3) synthase-dependent pathway. Reproduced with permission from Ref. [3].
EPS Components Biosynthesis pathway Properties Applications
Alginate GulA, ManA Synthase dependent Gelling capacity, film-forming ability Food, feed, medicine, research
Cellulose Glc Synthase dependent Not soluble in most solvents and high tensile strength Food, medicine, acoustics
Colanic acid Glc, Fuc, GlcA, Gal Wzx/Wzy dependent Gelling capacity N.a.
Curdlan Glc Synthase dependent Gel-forming ability, water insolubility, edible and nontoxic, has biological activity Food, cosmetics, medicine, construction chemistry
Diutan Glc, Rha, GlcA, Wzx/Wzy dependent High-molecular weight gum Construction chemistry
Gellan Glc, Rha, GlcA Wzx/Wzy dependent High viscosity and forms thermoreversible gels Construction chemistry, food, feed
Hyaluronic acid GlcA, GlcNAc Synthase dependent Gelling capacity, nontoxic Medicine, cosmetics
Succinoglycan Glc, Gal Wzx/Wzy dependent High viscosity and acid stability Oil industry, cosmetics
Welan Glc, Rha, GlcA, Man Wzx/Wzy dependent Stable in a wide pH range, viscosity retention at high temperature Construction chemistry
Xanthan Glc, Man, GlcA Wzx/Wzy dependent High viscosity, stable over a wide temperature, pH, and salt concentration ranges Food, feed, technical applications, oil drilling
Dextran Glc Extracellular, dextransucrase Nonionic, good stabilityNewtonian, fluid behavior Medicine, chromatography
Levan Fru, Glc Extracellular, levansucrase Does not swell in water, has low intrinsic viscosity, strong adhesive Food (prebiotic), feed, medicines, cosmetics, industry, glue
Tab.1  Overview of the important bacterial EPSs concerning monomer composition, biosynthesis pathway, and applications
Fig.2  Chemical structures of certain EPSs. (A) Dextran, (B) curdlan, (C) alginate, (D) pullulan, (E) hyaluronic acid, (F) cellulose.
Polymer Producing microorganism Chemical structure Reference
Microbial alginate Pseudomonas and Azotobacter [ 38]
Pullulan Fungus Aureobasidium, Fungus Tremella mesenterica, Rhodotorula bacarum, Hypovirulent strains of Cryphonectria parasitica, and C. parasitica [ 39]
Dextran Leuconostoc, Weissella, Lactobacillus, Streptococcus, and Leuconostoc mesenteroides [ 40]
Hyaluronic acid Streptococcus pyogenes, Streptococcus uberis, Pasteurella multocida, and Cryptococcus neoformans [ 41]
Bacterial cellulose Gram-negative bacteria species, such as Acetobacter, Azotobacter, Rhizobium, Pseudomonas, and Salmonella, Alcaligenes, and Gram-positive bacteria species, such as Sarcina ventriculi [ 42]
Tab.2  Microorganism-derived EPSs as functional biopolymers
Parameter Eur. Ph. 8.0 USP 32-NF 27
The appearance of the solid product White or pale yellowish-brown powder n.d.
Content n.d. 90.8%–106.0% of the dried basis
Packaging and storage n.d. Preserved in tight containers
Solubility Slowly soluble in water, practically insoluble in 96% ethanol n.d.
Appearance of solution Not more opalescent than reference formazin suspension in water and not more intensely colored than intensity 6 of the range of reference solutions of the most appropriate color n.d.
Heavy metals ≤20 ppm ≤ 0.004%
Chlorides ≤1.0% n.d.
Calcium ≤1.5% n.d.
Arsenic n.d. ≤ 1.5 ppm
Loss on drying ≤15.0% ≤ 15.0%
Total ash n.d. 18.0%–27.0%
Sulfated ash 30.0%–36.0% n.d.
Microbial limits TAMC: ≤1000 cfu/gTYMC: ≤100 cfu/g ≤ 200 cfu/g
Absence of specifiedmicroorganisms Salmonella sp.,Escherichia coli Salmonella sp., E. coli
Tab.3  Sodium alginate properties suggested by the European Pharmacopeia (Eur. Ph.) and the United States Pharmacopeia (USP) [131]
EPS’ type Additional material Scaffold type and fabrication technique Application Reference
Alginate Polyurethane and cobalt A hybrid cobalt-doped alginate/waterborne polyurethane 3D porous scaffold with nano-topology of a “coral reef-like” rough surface via two-step freeze–drying method Nerve repair [100]
Chitosan Using the lyophilization method, polypyrrole–alginate (PPy–Alg) mix is combined with chitosan to create polypyrrole–alginate (PPy–Alg) conducting scaffold Bone tissue engineering [101]
Poly (3,4-ethylenedioxythiophene) (PEDOT) Chemically cross-linked alginate networks are created in the PEDOT/Alg scaffold utilizing adipic acid hydrazide as the crosslinker, and PEDOT is generated in situ in the alginate matrix at the same time A platform for controlling cell behavior [102]
Bovine serum albumin and hydroxyapatite nanowires The freeze–dried hydrogel scaffold is immersed in an aqueous solution of CaCl2
A dual-network bovine serum albumin/sodium alginate with hydroxyapatite nanowires composite (B-S-H) hydrogel scaffold
Cartilage tissue engineering [103]
Poly (caprolactone) and CNC nanoparticles Poly (ε-caprolactone) (PCL)/CaAlg nanofibers are successfully produced using hybrid electrospinning Wound healing [104]
Cardiac ECM and chitosan Using freeze–drying method, cardiac tissue is prepared by decellularization technique, and the different concentrations of the solubilized ECM and chitosan/alginate are prepared and finally freeze-dried Cardiac tissue engineering [105]
Dextran β-tricalcium phosphate (β-TCP) A dextran nanocomposite hydrogelBy dispersion of β-TCP in the aqueous solution and adding epichlorohydrin (ECH) 12 v/v% as a chemical cross-linking agent Bone regeneration [106]
No Electrospun dextran nanofibers cross-linked using boric acid Wound dressing [107]
PVA and ciprofloxacin Core-shell nanofibers are fabricated by emulsion electrospinning from PVA/dextran As a drug delivery system [108]
Cellulose nanocrystal and gelatin Extrusion-based 3D printing method This hydrogel is suggested as a 3D bioink for application in tissue repair [109]
Pullulan PVA Aerogel composites are synthesized by impregnating nanofibrous pullulan-PVA scaffolds with hydrophobic silica aerogel Tissue regeneration [110]
Gelatin Electrospinning Tissue regeneration [111]
Collagen Hydrogel Wound healing [112]
Polyethyleneglycoldiacrylate (PEGDA) and methacrylic anhydride Hydrogel; photoinitiator is added to the solution to promote the (meth)acrylic units’ polymerization to PulMA and PEGDA through a radical mechanism Tissue adhesive scaffold with healing properties [113]
Poly (hydroxybutyrate-co-hydroxy valerate)/poly(ε-caprolactone) A multifunctional 3D fibrous scaffold fabricated by a co-electrospinning system As a drug delivery system for releasing cefuroxime axetil and also for bone regeneration [114]
HA Bacterial cellulose (BC) Cross-linked BC/HA compositesBC/HA composites are prepared by solution impregnation, and a chemical cross-linking is established in the BC/HA system by using 1,4-butanediol diglycidyl ether Wound healing [115]
ε-polylysine (EPL) as a natural antimicrobial peptide Electrospinning Wound healing [116]
Hyperbranched PEG An injectable hydrogel is reported by combining hyperbranched PEG-based multihydrazide macro-crosslinker and aldehyde-functionalized HA (HA-CHO), with gelatin added to increase the cross-linking density Tissue regeneration [117]
γ-poly (glutamic) acid (γ-PGA) and glycidyl methacrylate as the photo-crosslinker Digital light processing bio printed human chondrocyte-laden poly (γ-glutamic acid)/HA bio-ink Cartilage tissue engineering [118]
Bacterial cellulose ECH as a cross-linking agent The hydrogel is prepared by solving carboxymethyl-diethyl amino ethyl cellulose (CM-DEAEC) powder in deionized water and adding a cross-linking agent Drug delivery [119]
Graphene A novel scaffold for culturing neural stem cells (NSCs), three-dimensional bacterial cellulose−graphene foam, which is prepared via in situ bacterial cellulose interfacial polymerization on the skeleton surface of porous graphene foam Treatment of the neurodegenerative diseases [120]
Citric acid as a cross-linking agent Citric acid cross-linked carboxymethyl cellulose (C3CA) scaffolds are fabricated by a freeze–drying process Bone tissue engineering application [121]
ε-polylysine (ε-PL), mussel-inspired polydopamine (PDA) BC membranes are coated with PDA by a simple self-polymerization process, followed by treating with different contents of ε-PL Wound dressing [122]
PVA Composite hydrogel Substitute for corneal stroma [123]
Bacteriophages Carbon Wild M13 bacteriophage particles are used for CNF electrode modification Surface modification [124]
Polycaprolactone and collagen Electrospinning Wound dressing with antibacterial hemostatic dual-function properties [125]
Chitosan and alginate Microencapsulation procedure Therapeutic phage by oral delivery [126]
Alginate and poly ε-caprolactone A hybrid scaffold consisting of microsized core-sheath struts based on chemically conjugated M13 bacteriophage (phage)/alginate and PCL Bone tissue regeneration [127]
Tab.4  Some examples for using exopolysaccharides in the field of tissue engineering
Fig.3  Cells detach from the dextran-based thermoresponsive membrane without using any enzyme. Dextran-allyl isocyanate-ethylamine is a biodegradable, thermoresponsive polymer presented for detaching cells. Above LCST, dextran-allyl isocyanate-ethylamine is hydrophobic, and cells adhere to it. Below LCST, it becomes hydrophilic and nonadhesive to cells. LCST, lower critical solution temperature; T, temperature; TSP, thermosensitive polymer. Reproduced with permission from Ref. [129].
Fig.4  IPC fibers are created and then incorporated into a polysaccharide scaffold. (A) IPC fibers are formed by pulling oppositely charged polyelectrolytes together. (B) Illustration of an IPC fiber gathered with a pair of collecting needles. (C) The IPC fibers are incorporated into the PD to produce a composite scaffold. (D) Lyophilized polysaccharide scaffold. Reproduced with permission from Ref. [77].
Fig.5  3D bioplotting of alginate hydrogels. (A) Schwann cells are first mixed with alginate hydrogels and then bioplotted. (B) Cell-loaded alginate constructs and staining conclusion showing one strand. (C) Using a 100 μm needle for printing 0.5% alginate with poor printability and staining of the cell-loaded gel. Reproduced with permission from Ref. [85].
Fig.6  Indirect biofabrication. (A) 3D bioplotter applied to the development of gelatin scaffold. (B) Gelatin construct and bulk gel models. (C) Gelatin scaffold and a close view of this sacrificial framework. Reproduced with permission from Ref. [85].
Fig.7  (A) 3D printed model of nano cellulose–alginate scaffold. (B) The scaffold distorts under compression, but (C) returns to its original form after the pressure is completely removed. (D) Bioprinted human ear. (E and F) Sheep meniscus constructs. Reproduced with permission from Ref. [130].
Fig.8  (A)(a) Photomicrograph of the composite hydrogels based on HP/PVA produced using a freeze–thawing technique. (b) SEM microphotographs of the HP/PVA hydrogels [90]. (B)(a–c) Synthesis of carboxymethyl pullulan, CMP-TA, and CS-TA. (d) Hydrogel formation from CMP-TAs and CS-TAs via HRP-mediated cross-linking in the presence of H2O2 [92]. Reproduced with permission from Refs. [90, 92].
Fig.9  M13 phage binds CNFs with a point mutation in the pVII protein (pVII mutant-M13). Reproduced with permission from Ref. [96] ( Copyright © 2016, American Chemical Society).
Fig.10  Display of a collagen-like peptide (GPP)8 on flagella, biomimetic assembly and mineralization of the resultant GPP8 flagella, and BMSCs’ differentiation on the GPP8 flagella film. Reproduced with permission from Ref. [99].
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