Abstract
Biopolymeric polyhydroxyalkanoates (PHAs) are fabricated and accumulated by microbes under unbalanced growth conditions, primarily by diverse genera of bacteria. Over the last two decades, microbially engineered PHAs gained substantial interest worldwide owing to their promising wide-range uses in biomedical field as biopolymeric biomaterials. Because of non-hazardous disintegration products, preferred surface alterations, inherent biocompatibility, modifiable mechanical properties, cultivation support for cells, adhesion devoid of carcinogenic impacts, and controllable biodegradability, the PHAs like poly-3-hydroxybutyrate, 3-hydroxybutyrate and 3-hydroxyvalerate co-polymers, 3-hydroxybutyrate and 4-hydroxybutyrate co-polymers, etc., are available for various medical applications. These PHAs have been exploited to design in vivo implants like sutures as well as valves for direct tissue repairing as well as in regeneration devices like bone graft substitutes, nerve guides as well as cardiovascular patches, etc. Furthermore, they are also emerged as attractive candidates for developing effective/novel drug delivery systems because of their biocompatibility and biodegradability with the ability to deliver and release the drugs at a specific site in a controllable manner and, therefore widen the therapeutic window with reduced side effects. However, there still remain some bottlenecks related to PHA purity, mechanical properties, biodegradability, etc., that are need to be addressed so as to make PHAs a realistic biomaterial. In addition, innovative approaches like PHAs co-production with other value-added products, etc., must be developed currently for economical PHA production. This review provides an insight toward the recent advances, bottlenecks, and potential solutions for prospective biomedical applications of PHAs with conclusion that relatively little research/study has been performed presently toward the viability of PHAs as realistic biopolymeric biomaterials.
Similar content being viewed by others
References
Abdelwahab MA, El-Barbary AA, El-Said KS, El Naggar SA, ElKholy HM (2019) Evaluation of antibacterial and anticancer properties of poly(3-hydroxybutyrate) functionalized with different amino compounds. Int J Biol Macromol 122:793–805
Ali I, Jamil N (2016) Polyhydroxyalkanoates: current applications in the medical field. Front Biol 11:19–27
Alves LP, Teixeira CS, Tirapelle EF, Donatti L, Tadra-Sfeir MZ, Steffens MB, de Souza EM, de Oliveira PF, Chubatsu LS, Müller-Santos M (2016) Backup expression of the PhaP2 Phasin compensates for phaP1 deletion in Herbaspirillum seropedicae, maintaining fitness and PHB accumulation. Front Microbiol 7:739
Anjum A, Zuber M, Zia KM, Noreen A, Anjum MN, Tabasum S (2016) Microbial production of polyhydroxyalkanoates (PHAs) and its copolymers: a review of recent advancements. Int J Biol Macromol 89:161–174
Ansari NF, Annuar MSM (2018) Functionalization of medium-chain-length poly (3-hydroxyalkanoates) as amphiphilic material by graft copolymerization with glycerol 1, 3-diglycerolate diacrylate and its mechanism. J Macromol Sci A 55:66–74
Basnett P, Ching KY, Stolz M, Knowles JC, Boccaccini AR, Smith C, Locke IC, Keshavarz T, Roy I (2013) Novel poly (3-hydroxyoctanoate)/poly (3-hydroxybutyrate) blends for medical applications. React Funct Polym 73:1340–1348
Benavente J, Vazquez MI (2004) Effect of age and chemical treatments on characteristic parameters for active and porous sublayers of polymeric composite membranes. J Colloid Interface Sci 273:547–555
Bhatia SK, Wadhwa P, Hong JW, Hong YG, Jeon JM, Lee ES, Yang YH (2019) Lipase mediated functionalization of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with ascorbic acid into an antioxidant active biomaterial. Int J Biol Macromol 123:117–123
Bhattacharya S, Dubey S, Singh P, Shrivastava A, Mishra S (2016) Biodegradable polymeric substances produced by a marine bacterium from a surplus stream of the biodiesel industry. Bioengineering 3:34–44
Bissery MC, Valeriote F, Thies C (1985) Therapeutic efficacy of CCNU-loaded microspheres prepared from poly(D,L)lactide (PLA) or poly-b-hydroxybutyrate (PHB) against Lewis lung (LL) carcinoma. Proc Am Assoc Cancer Res 26:355–355
Bonthrone KM, Clauss J, Horowitz DM, Hunter BK, Sanders JKM (1992) The biological and physical chemistry of polyhydroxyalkanoates as seen by NMR spectroscopy. FEMS Microbiol Rev 10:269–278
Bowald SF, Johansson EG (1990) A novel surgical material. European Patent No. 0349505A2
Brandl H, Gross RA, Lenz RW, Fuller RC (1990) Plastics from bacteria and for bacteria: poly(β-hydroxyalkanoates) as natural, biocompatible, and biodegradable polyesters. Adv Biochem Eng Biotechnol 41:77–93
Brigham CJ, Sinskey AJ (2012) Applications of polyhydroxyalkanoates in the medical industry. Int J Biotechnol Wellness Ind 1:53–60
Brzeska J, Heimowska A, Janeczek H, Kowalczuk M, Rutkowska M (2014) Polyurethanes based on atactic poly[(R,S)-3-hydroxybutyrate]: preliminary degradation studies in simulated body fluids. J Polym Environ 22:176–182
Bugnicourt E, Cinelli P, Lazzeri A, Alvarez V (2014) Polyhydroxyalkanoate (PHA): review of synthesis, characteristics, processing and potential applications in packaging. Express Polym Lett 8:791–808
Byrom D (1987) Polymer synthesis by microorganisms: technology and economics. Trends Biotechnol 5:246–250
Cao Q, Zhang J, Liu H, Wu Q, Chen J, Chen GQ (2014) The mechanism of anti-osteoporosis effects of 3-hydroxybutyrate and derivatives under simulated microgravity. Biomaterials 35:8273–8283
Caon T, Berezina N, Lin CSK, Fakhouri FM, Martelli SM (2014) Polyhydroxyalkanoates and their potential in controlled-release drug delivery systems: biomedical applications and factors affecting the drug release. In: Linping W (ed) Polyhydroxyalkanoates (PHAs): biosynthesis, industrial production and applications in medicine. Nova Science Publishers, Inc., Hauppauge, p 219–236
Capulli AK, Emmert MY, Pasqualini FS, Kehl D, Caliskan E, Lind JU, Sheehy SP, Park SJ, Ahn S, Weber B, Goss JA, Hoerstrup SP, Parker KK (2017) JetValve: rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement. Biomaterials 133:229–241
Carr NG (1966) The occurrence of poly-β-hydroxybutyrate in the blue-green alga, Chlorogloea fritschii. Biochem Biophys Acta 120:308–310
Castilho LR, Mitchell DA, Freire DMG (2009) Production of polyhydroxyalkanoates (PHAs) from waste materials and by-products by submerged and solid-state fermentation. Bioresour Technol 100:5996–6009
Chandel AK, Garlapati VK, Singh AK, Antunes FAF, da Silva SS (2018) The path forward for lignocellulose biorefineries: bottlenecks, solutions, and perspective on commercialization. Bioresour Technol 264:370–381
Chaput C, Yahia LH, Selmani A, Rivard C-H (1995) Natural poly(hydroxybutyrate-hydroxyvalerate) polymers as degradable biomaterials. Mat Res Soc Symp Proc 385:49–54
Chen W, Tong YW (2012) PHBV microspheres as neural tissue engineering scaffold support neuronal cell growth and axon–dendrite polarization. Acta Biomater 8:540–548
Chen G-Q, Wu Q (2005) The application of polyhydroxyalkanoates as tissue engineering materials. Biomaterials 26:6565–6578
Chen G-Q, Zhang J (2017) Microbial polyhydroxyalkanoates as medical implant biomaterials. Artif Cells Nanomed Biotechnol 46:1–18
Chen Y, Tsai Y, Chou IN, Tseng SH, Wu HS (2014) Application of biodegradable polyhydroxyalkanoates as surgical films for ventral hernia repair in mice. Int J Polym Sci 2014:789681
Choi J, Lee SY (1999) Factors affecting the economics of polyhydroxyalkanoate production by bacterial fermentation. Appl Microbiol Biotechnol 51:13–21
Chuah JA, Yamada M, Taguchi S, Sudesh K, Doi Y, Numata K (2013) Biosynthesis and characterization of polyhydroxyalkanoate containing 5-hydroxyvalerate units: effects of 5HV units on biodegradability, cytotoxicity, mechanical and thermal properties. Polym Degrad Stab 98:331–338
Chung CW, Kim HW, Kim YB, Rhee YH (2003) Poly(ethylene glycol)-grafted poly(3-hydroxyundecenoate) networks for enhanced blood compatibility. Int J Biol Macromol 32:17–22
Czech Republic (2015) http://www.psi.cz/products/photobioreactors. Accessed 14 Dec 2018
Del Gaudio C, Fioravanzo L, Folin M, Marchi F, Ercolani E, Bianco A (2012) Electrospun tubular scaffolds: on the effectiveness of blending poly(e-caprolactone) with poly(3-hydroxybutyrate-co-3-hydroxyvalerate). J Biomed Mater Res B Appl Biomater 100:1883–1898
Devi ES, Vijayendra SVN, Shamala TR (2012) Exploration of rice bran, an agro-industry residue, for the production of intra-and extra-cellular polymers by Sinorhizobium meliloti MTCC 100. Biocatal Agric Biotechnol 1:80–84
DiGregorio BE (2009) Biobased performance bioplastic: Mirel. Chem Biol 16:1–2
Dinjaski N, Fernández-Gutiérrez M, Selvam S, Parra-Ruiz FJ, Lehman SM, San Román J, García E, García JL, García AJ, Prieto MA (2014) PHACOS, a functionalized bacterial polyester with bactericidal activity against methicillin-resistant Staphylococcus aureus. Biomaterials 35:14–24
Dumaz N, Drougard C, Sarasin A, Daya-Grosjean L (1993) Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci U S A 90:10529–10533
Durai P, Batool M, Choi S (2015) Structure and effects of cyanobacterial lipopolysaccharides. Mar Drugs 13:4217–4230
Emmert MY, Weber B, Behr L, Sammut S, Frauenfelder T, Wolint P, Scherman J, Bettex D, Grünenfelder J, Falk V, Hoerstrup SP (2014) Transcatheter aortic valve implantation using anatomically oriented, marrow stromal cell-based, stented, tissue-engineered heart valves: technical considerations and implications for translational cell-based heart valve concepts. Eur J Cardiothorac Surg 45:61–68
Fava F, Totaro G, Gavrilescu M (2015) Material & energy recovery and sustainable development, ECOMONDO 2014. Environ Eng Manag J 14:1475–1471
Fu X-Z, Tan D, Aibaidula G, Wu Q, Chen J-C, Chen G-Q (2014) Development of Halomonas TD01 as a host for open production of chemicals. Metab Eng 23:78–91
Furrer P, Panke S, Zinn M (2007) Efficient recovery of low endotoxin medium-chain-length poly([R]-3-hydroxyalkanoate) from bacterial biomass. J Microbiol Methods 69:206–213
Furrer P, Zinn M, Panke S (2008) Polyhydroxyalkanoate and its potential for biomedical applications. In: Reis RL, Neves NM, Mano JF, Gomes ME, Marques AP, Azevedo HS (eds) Natural-based polymers for biomedical applications. Elsevier, Amsterdam, pp 416–445
Gardel M, Schwarz U (2010) Cell–substrate interactions. J Phys Condens Matter 22:190301
Geiger B, Spatz JP, Bershadsky AD (2009) Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10:21–33
Gould PL, Holland SJ, Tighe BJ (1987) Polymers for biodegradable medical devices. IV. Hydroxybutyrate-valerate copolymers as non-disintegrating matrices for controlled release oral dosage forms. Int J Pharm 38:231–237
Gu P, Kang J, Yang F, Wang Q, Liang Q, Qi Q (2013) The improved L-tryptophan production in recombinant Escherichia coli by expressing the polyhydroxybutyrate synthesis pathway. Appl Microbiol Biotechnol 97:4121–4127
Gursel I, Korkusuz F, Turesin F, Gurdal Alaeddinoglu N, Hasirci V (2001) In vivo application of biodegradable controlled antibiotic release systems for the treatment of implant-related osteomyelitis. Biomaterials 22:73–80
Hazari A, Johansson-Ruden G, Bostrom KJ, Ljungberg C, Terenghi G, Green C, Wiberg M (1999a) A new resorbable wrap around implant as an alternative nerve repair technique. J Hand Surg Br 24B:291–295
Hazari A, Wiberg M, Johansson-Ruden G, Green C, Terenghi G (1999b) A resorbable nerve conduit as an alternative to nerve autograft in nerve gap repair. Br J Plast Surg 52:653–657
Hazer B, Steinbüchel A (2007) Increased diversification of polyhydroxyalkanoates by modification reactions for industrial and medical applications. Appl Microbiol Biotechnol 74:1–12
Hazer DB, Kiliçay E, Hazer B (2012) Poly(3-hydroxyalkanoate)s: diversification and biomedical applications: a state of the art review. Mater Sci Eng C 32:637–647
He Y, Hu Z, Ren M, Ding C, Chen P, Gu Q, Wu Q (2014) Evaluation of PHBHHx and PHBV/PLA fibers used as medical sutures. J Mater Sci Mater Med 25:561–571
Hollstein M, Sidransky D, Vogelstein B, Harris C (1991) p53 mutations in human cancers. Science 253:49–53
Hu YJ, Wei X, Zhao W, Liu YS, Chen GQ (2009) Biocompatibility of poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) with bone marrow mesenchymal stem cells. Acta Biomater 5:1115–1125
Inan K, Sal FA, Rahman A, Putman RJ, Agblevor FA, Miller CD (2016) Microbubble assisted polyhydroxybutyrate production in Escherichia coli. BMC Res Notes 9:338
Insomphun C, Chuah JA, Kobayashi S, Fujiki T, Numata K (2017) Influence of hydroxyl groups on the cell viability of polyhydroxyalkanoate (PHA) scaffolds for tissue engineering. ACS Biomater Sci Eng 3:3064–3075
Janousek P, Kabelka Z, Rygl M, Lesný P, Grabec P, Fajstavr J, Jurovcík M, Snajdauf J (2006) Corrosive injury of the oesophagus in children. Int J Pediatr Otorhinolaryngol 70:1103–1107
Jendrossek D, Pfeiffer D (2014) New insights in the formation of polyhydroxyalkanoate granules (carbonosomes) and novel functions of poly(3-hydroxybutyrate). Environ Microbiol 16:2357–2373
Ji Y, Li XT, Chen GQ (2008) Interactions between a poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) terpolyester and human keratinocytes. Biomaterials 29:3807–3814
Jiang X, Ramsay JA, Ramsay BA (2006) Acetone extraction of mcl-PHA from Pseudomonas putida KT2440. J Microbiol Methods 67:212–219
Kai D, Loh XJ (2014) Polyhydroxyalkanoates: chemical modifications toward biomedical applications. ACS Sustain Chem Eng 2:106–119
Kang Z, Du L, Kang J, Wang Y, Wang Q, Liang Q, Qi Q (2011) Production of succinate and polyhydroxyalkanoate from substrate mixture by metabolically engineered Escherichia coli. Bioresour Technol 102:6600–6604
Koller M, Maršálek L (2015) Cyanobacterial polyhydroxyalkanoate production: status quo and quo Vadis? Curr Biotechnol 4:464–480
Kumar A, Srivastava JK, Mallick N, Singh AK (2015) Commercialization of bacterial cell factories for the sustainable production of polyhydroxyalkanoate thermoplastics: progress and prospects. Recent Pat Biotechnol 9:4–21
Kuroda K, Caputo GA (2013) Antimicrobial polymers as synthetic mimics of host-defense peptides. Interdiscip Rev Nanomed Nanobiotechnol 5:49–66
Leal-Egaña, Díaz-Cuenca A, Boccaccini AR (2013) Tuning of cell-biomaterial anchorage for tissue regeneration. Adv Mater 25:4049–4057
Lee SY, Choi JI, Han K, Song JY (1999) Removal of endotoxin during purification of poly(3–hydroxybutyrate) from gram-negative bacteria. Appl Environ Microbiol 65:2762–2764
Lee J, Jung SG, Park CS, Kim HY, Batt CA, Kim YR (2011) Tumor-specific hybrid polyhydroxybutyrate nanoparticle: surface modification of nanoparticle by enzymatically synthesized functional block copolymer. Bioorg Med Chem Lett 21:2941–2944
Lenz RW, Marchessault RH (2005) Bacterial polyesters: biosynthesis, biodegradable plastics and biotechnology. Biomacromolecules 6:1–8
Levine AC, Sparano A, Twigg FF, Numata K, Nomura CT (2015) Influence of cross-linking on the physical properties and cytotoxicity of polyhydroxyalkanoate (PHA) scaffolds for tissue engineering. ACS Biomater Sci Eng 1:567–576
Li Z, Loh XJ (2015) Water soluble polyhydroxyalkanoates: future materials for therapeutic applications. Chem Soc Rev 44:2865–2879
Li J, Yun H, Gong Y, Zhao N, Zhang X (2005) Effects of surface modification of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) on physicochemical properties and on interactions with MC3T3-E1 cells. J Biomed Mater Res A 75:985–998
Li X, Chang H, Luo H, Wang Z, Zheng G, Lu X, He X, Chen F, Wang T, Liang J, Xu M (2015) Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds coated with PhaP-RGD fusion protein promotes the proliferation and chondrogenic differentiation of human umbilical cord mesenchymal stem cells in vitro. J Biomed Mater Res A 103:1169–1175
Li X, Li X, Chen D, Guo J-L, Feng D-F, Sun M-Z, Lu Y, Chen D-Y, Zhao X, Feng X-Z (2016a) Evaluating the biological impact of polyhydroxyalkanoates (PHAs) on developmental and exploratory profile of zebrafish larvae. RSC Adv 6:37018–37030
Li Z, Yang J, Loh XJ (2016b) Polyhydroxyalkanoates: opening doors for a sustainable future. NPG Asia Mater 8:e265
Li T, Guo YY, Qiao GQ, Chen GQ (2016c) Microbial synthesis of 5-aminolevulinic acid and its coproduction with polyhydroxybutyrate. ACS Synth Biol 5:1264–1274
Li T, Ye J, Shen R, Zong Y, Zhao X, Lou C, Chen G-Q (2016d) Semirational approach for ultrahigh poly(3-hydroxybutyrate) accumulation in Escherichia coli by combining one-step library construction and high-throughput screening. ACS Synth Biol 5:1308–1317
Li T, Elhadi D, Chen GQ (2017) Co-production of microbial polyhydroxyalkanoates with other chemicals. Metab Eng 43:29–36
Liang Q, Qi Q (2014) From a co-production design to an integrated single-cell biorefinery. Biotechnol Adv 32:1328–1335
Licciardello G, Ferraro R, Russo M, Strozzi F, Catara AF, Bella P, Catara V (2016) Transcriptome analysis of Pseudomonas mediterranea and P. corrugata plant pathogens during accumulation of medium-chain-length PHAs by glycerol bioconversion. New Biotechnol 37:39–47
Liu S, Zhang G, Li X, Zhang J (2014) Microbial production and applications of 5-aminolevulinic acid. Appl Microbiol Biotechnol 98:7349–7357
Lizarraga-Valderrama LR, Nigmatullin R, Taylor C, Haycock JW, Claeyssens F, Knowles JC, Roy I (2015) Nerve tissue engineering using blends of poly (3-hydroxyalkanoates) for peripheral nerve regeneration. Eng Life Sci 15:612–621
Ljungberg C, Johansson RG, Bostrom KJ, Novikov L, Weiberg M (1999) Neuronal survival using a resorbable synthetic conduit as an alternative to primary nerve repair. Microsurgery 19:250–264
Löbler M, Saß M, Schmitz KP, Hopt UT (2002) Biomaterial implants induce the inflammation marker CRP at the site of implantation. J Biomed Mater Res 61:165–167
Loh XJ, Wang X, Li H, Li X, Li J (2007) Compositional study and cytotoxicity of biodegradable poly(ester urethane)s consisting of poly[(R)-3-Hydroxybutyrate] and poly(ethylene glycol). Mater Sci Eng C 27:267–273
Lomas AJ, Webb WR, Han J, Chen GQ, Sun X, Zhang Z, El Haj AJ, Forsyth NR (2013) Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)/collagen hybrid scaffolds for tissue engineering applications. Tissue Eng Part C Methods 19:577–585
Lu X-Y, Ciraolo E, Stefenia R, Chen G-Q, Zhang Y, Hirsch E (2011) Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines. Appl Microbiol Biotechnol 89:1423–1433
Lu X, Wang L, Yang Z, Lu H (2013) Strategies of polyhydroxyalkanoates modification for the medical application in neural regeneration/nerve tissue engineering. Adv Biosci Biotechnol 4:731–740
Lu HX, Yang ZQ, Jiao Q, Wang YY, Wang L, Yang PB, Chen XL, Zhang PB, Wang P, Chen MX, Lu XY, Liu Y (2014) Low concentration of serum helps to maintain the characteristics of NSCs/NPCs on alkali-treated PHBHHx film in vitro. Neurol Res 36:207–214
M & M (2018) Markets and Markets Polyhydroxyalkanoate (PHA) Market by Type (Monomers, Co-Polymers, Terpolymers), Manufacturing Technology (Bacterial Fermentation, Biosynthesis, Enzymatic Catalysis), Application (Packaging, Bio Medical, Food Services, Agriculture)—Global Forecast to 2021 (Available online: http://www.marketsandmarkets.com/Market-Reports/pha-market-395.html (accessed on 10 December, 2018)
Ma Z, Gao C, Gong Y, Shen J (2003) Chondrocyte behaviors on poly-L-lactic acid (PLLA) membranes containing hydroxyl, amide or carboxyl groups. Biomaterials 24:3725–3730
Mallick N, Sharma L, Singh AK (2007) Poly-β-hydroxybutyrate accumulation in Nostoc muscorum: effects of metabolic inhibitors. J Plant Physiol 164:312–317
Martínez V, García P, García JL, Prieto MA (2011) Controlled autolysis facilitates the polyhydroxyalkanoate recovery in Pseudomonas putida KT2440. Microb Biotechnol 4:533–547
Masood F, Chen P, Yasin T, Fatima N, Hasan F, Hameed A (2013) Encapsulation of ellipticine in poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) based nanoparticles and its in vitro application. Mater Sci Eng C Mater 33:1054–1060
Masood F, Yasin T, Hameed A (2015) Polyhydroxyalkanoates—what are the uses? Current challenges and perspectives. Crit Rev Biotechnol 35:514–521
Mergaert J, Anderson C, Wouters A, Swings J, Kersters K (1992) Biodegradation of polyhydroxyalkanoates. FEMS Microbiol Rev 10:317–322
Montazeri M, Karbasi S, Foroughi M, Monshi A, Ebrahimi-Kahrizsangi R (2015) Evaluation of mechanical property and bioactivity of nano-bioglass 45S5 scaffold coated with poly-3-hydroxybutyrate. J Mater Sci Mater Med 26:62
Nair LS, Laurencin CT (2006) Polymers as biomaterials for tissue engineering and controlled drug delivery. Adv Biochem Eng Biotechnol 102:47–90
Nigmatullin R, Thomas P, Lukasiewicz B, Puthussery H, Roy I (2015) Polyhydroxyalkanoates, a family of natural polymers, and their applications in drug delivery. J Chem Technol Biotechnol 90:1209–1221
Noble JR, Zhong ZH, Neumann AA, Melki JR, Clark SJ, Reddel RR (2004) Alterations in the p16INK4a and p53 tumor suppressor genes of hTERT-immortalized human fibroblasts. Oncogene 23:3116–3121
Obruca S, Sedlacek P, Koller M, Kucera D, Pernicova I (2018) Involvement of polyhydroxyalkanoates in stress resistance of microbial cells: biotechnological consequences and applications. Biotechnol Adv 36:856–870
Opitz F, Schenke-Layland K, Richter W, Martin DP, Degenkolbe I, Wahlers T, Stock UA (2004) Tissue engineering of ovine aortic blood vessel substitutes using applied shear stress and enzymatically derived vascular smooth muscle cells. Ann Biomed Eng 32:212–222
Pelham RJ Jr, Wang Y (1997) Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci USA 94:13661–13665
Peng SW, Guo XY, Shang GG, Li J, Xu XY, You ML, Li P, Chen GQ (2011) An assessment of the risks of carcinogenicity associated with polyhydroxyalkanoates through an analysis of DNA aneuploid and telomerase activity. Biomaterials 32:2546–2555
Peptu C, Kowalczuk M (2018) Biomass-derived polyhydroxyalkanoates: biomedical applications. In: Popa V, Volf I (eds) Biomass as renewable raw material to obtain bioproducts of high-tech value. Elsevier, Peptu, p 271–313
Plastics Technology (2017) http://www.ptonline.com/articles/prices-bottom-out-forpolyolefins-pet-ps-pvc-move-up (accessed on 10 December, 2018)
Pramanik N, Bhattacharya S, Rath T, De J, Adhikary A, Basu RK, Kundu PP (2019) Polyhydroxybutyrate-co-hydroxyvalerate copolymer modified graphite oxide based 3D scaffold for tissue engineering application. Mater Sci Eng C 94:534–546
Pramual S, Assavanig A, Bergkvist M, Batt CA, Sunintaboon P, Lirdprapamongkol K, Svasti J, Niamsiri N (2016) Development and characterization of bio-derived polyhydroxyalkanoate nanoparticles as a delivery system for hydrophobic photodynamic therapy agents. J Mater Sci Mater Med 27:40
Qu XH, Wu Q, Liang J, Qu X, Wang SG, Chen GQ (2005) Enhanced vascular-related cellular affinity on surface modified copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx). Biomaterials 26:6991–7001
Qu XH, Wu Q, Zhang KY, Chen GQ (2006) In vivo studies of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) based polymers: biodegradation and tissue reactions. Biomaterials 27:3540–3548
Rai R, Yunos DM, Boccaccini AR, Knowles JC, Barker IA, Howdle SM, Tredwell GD, Keshavarz T, Roy I (2011) Poly-3hydroxyoctanoate P(3HO): a medium chain length polyhydroxyalkanoate homopolymer from Pseudomonas mendocina. Biomacromolecules 12:2126–2136
Rajaratanam DD, Ariffin H, Hassan MA, Nik Abd Rahman NMA, Nishida H (2018) In vitro cytotoxicity of superheated steam hydrolyzed oligo((R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate) and characteristics of its blend with poly(L-lactic acid) for biomaterial applications. PLoS ONE 13:e0199742
Rashid NFM, Azemi MAFM, Amiru AAA, Wahid MEA, Bhubalan K (2015) Simultaneous production of biopolymer and biosurfactant by genetically modified Pseudomonas aeruginosa UMTKB-5. Conference: international proceedings of chemical, biological and environmental engineering, Auckland, New Zealand, 90:3−8
Rathbone S, Furrer P, Lübben J, Zinn M, Cartmell SJ (2010) Biocompatibility of polyhydroxyalkanoate as a potential material for ligament and tendon scaffold material. J Biomed Mater Res A 93:1391–1403
Raza ZA, Riaz S, Banat IM (2018) Polyhydroxyalkanoates: properties and chemical modification approaches for their functionalization. Biotechnol Prog 34:29–41
Ren Y, Wang C, Qiu Y (2008) Aging of surface properties of ultra high modulus polyethylene fibers treated with He/O atmospheric pressure plasma jet. Surf Coat Technol 202:2670–2676
Ren Q, Ruth K, Thöny-Meyer L, Zinn M (2010) Enatiomerically pure hydroxycarboxylic acids: current approaches and future perspectives. Appl Microbiol Biotechnol 87:41–52
Ricotti L, Polini A, Genchi GG, Ciofani G, Iandolo D, Vazão H, Mattoli V, Ferreira L, Menciassi A, Pisignano D (2012) Proliferation and skeletal myotube formation capability of C2C12 and H9c2 cells on isotropic and anisotropic electrospun nanofibrous PHB scaffolds. Biomed Mater 7:035010
Saito T, Tomita K, Juni K, Ooba K (1991) In vivo and in vitro degradation of poly(3-hydroxybutyrate) in rat. Biomaterials 12:309–312
Samantaray S, Mallick N (2014) Production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) co-polymer by the diazotrophic cyanobacterium Aulosira fertilissima CCC 444. J Appl Phycol 26:237–245
Samantaray S, Mallick N (2015) Impact of various stress conditions on poly-β-hydroxybutyrate (PHB) accumulation in Aulosira fertilissima CCC 444. Curr Biotechnol 4:366–372
Sankhla SS, Bhati R, Singh AK, Mallick N (2010) Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) copolymer production from a local isolate, Brevibacillus invocatus MTCC 9039. Biores Technol 101:1947–1953
Schmidt CE, Leach JB (2003) Neural tissue engineering: strategies for repair and regeneration. Ann Rev Biomed Eng 5:293–347
Sevastianov VI, Perova NV, Shishatskaya EI, Kalacheva GS, Volova TG (2003) Production of purified polyhydroxyalkanoates (PHAs) for applications in contact with blood. J Biomater Sci Polym Ed 14:1029–1042
Shah M, Ullah N, Choi MH, Kim MO, Yoon SC (2012) Amorphous amphiphilic P(3HV-co-4HB)-b-mPEG block copolymer synthesized from bacterial copolyester via melt transesterification: nanoparticle preparation, cisplatin loading for cancer therapy and in vitro evaluation. Eur J Pharm Biopharm 80:518–527
Shah AA, Kato S, Shintani N, Kamini NR, Nakajima-Kambe T (2014) Microbial degradation of aliphatic and aliphatic-aromatic co-polyesters. Appl Microbiol Biotechnol 98:3437–3447
Shangguan YY, Wang YW, Wu Q, Chen GQ (2006) The mechanical properties and in vitro biodegradation and biocompatibility of UV-treated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). Biomaterials 27:2349–2357
Sharma L, Panda B, Singh AK, Mallick N (2006) Studies on poly-β-hydroxybutyrate synthase activity of Nostoc muscorum. J Gen Appl Microbiol 52:209–214
Sharma L, Singh AK, Panda B, Mallick N (2007) Process optimization for poly-β-hydroxybutyrate production in a nitrogen fixing cyanobacterium, Nostoc muscorum using response surface methodology. Bioresour Technol 98:987–993
Sharma L, Srivastava JK, Singh AK (2016) Biodegradable polyhydroxyalkanoate thermoplastics substituting xenobiotic plastics: a way forward for sustainable environment. In: Singh A, Prasad SM, Singh RP (eds) Plant responses to xenobiotics. Springer-Verlag, New York, pp 317–346
Shen F, Zhang E, Wei Z (2010) In vitro blood compatibility of poly (hydroxybutyrate-co-hydroxyhexanoate) and the influence of surface modification by alkali treatment. Mater Sci Eng C 30:369–375
Shishatskaya EI, Volova TG, Gitelson II (2002) In vivo toxicological evaluation of polyhydroxyalkanoates. Dokl Biol Sci 383:109–111
Shishatskaya EI, Volova TG, Puzyr AP, Mogilnaya OA, Efremov SN (2004) Tissue response to the implantation of biodegradable polyhydroxyalkanoate sutures. J Mater Sci Mater Med 15:719–728
Shishatskaya EI, Volova TG, Gordeev SA, Puzyr AP (2005) Degradation of P(3HB) and P(3HB-co-3HV) in biological media. J Biomater Sci Polymer Edn 16:643–657
Shrivastav A, Kim HY, Kim YR (2013) Advances in the applications of polyhydroxyalkanoate nanoparticles for novel drug delivery system. Biomed Res Int 2013:581684
Singh AK, Mallick N (2008) Enhanced production of SCL-LCL-PHA co-polymer by sludge-isolated Pseudomonas aeruginosa MTCC 7925. Lett Appl Microbiol 46:350–357
Singh AK, Mallick N (2009a) Exploitation of inexpensive substrates for production of a novel SCL-LCL-PHA co-polymer by Pseudomonas aeruginosa MTCC 7925. J Ind Microbiol Biotechnol 36:347–354
Singh AK, Mallick N (2009b) SCL-LCL-PHA copolymer production by a local isolate, Pseudomonas aeruginosa MTCC 7925. Biotechnol J 4:703–711
Singh AK, Mallick N (2016) Biological system as reactor for production of biodegradable thermoplastics, polyhydroxyalkanoates. In: Thangadurai D, Sangeetha J (eds) Industrial biotechnology: sustainable production and bioresource utilization. CRC Press Taylor and Francis, USA, pp 281–323
Singh AK, Mallick N (2017) Advances in cyanobacterial polyhydroxyalkanoates production. FEMS Microbiol Lett 364(20). https://doi.org/10.1093/femsle/fnx189
Singh AK, Bhati R, Samantaray S, Mallick N (2013a) Pseudomonas aeruginosa MTCC 7925: producer of a novel SCL-LCL-PHA co-polymer. Curr Biotechnol 2:81–88
Singh M, Kumar P, Patel SKS, Kalia VC (2013b) Production of polyhydroxyalkanoate co-polymer by Bacillus thuringiensis. Indian J Microbiol 53:77–83
Singh AK, Ranjana B, Mallick N (2015) Pseudomonas aeruginosa MTCC 7925 as a biofactory for production of the novel SCL-LCL-PHA thermoplastic from non-edible oils. Curr Botechnol 4:65–74
Singh AK, Sharma L, Mallick N, Mala J (2017) Progress and challenges in producing polyhydroxyalkanoate biopolymers from cyanobacteria. J Appl Phycol 29:1213–1232
Singh AK, Sharma L, Srivastava JK, Mallick N, Ansari MI (2018) Microbially originated polyhydroxyalkanoate (PHA) biopolymers: an insight into the molecular mechanism and biogenesis of PHA granules. In: Singh OV, Chandel AK (eds) Sustainable biotechnology-enzymatic resources of renewable energy. Springer, Cham, pp 355–398
Sodian R, Hoerstrup SP, Sperling JS, Daebritz S, Martin DP, Moran AM, Kim BS, Schoen FJ, Vacanti JP, Mayer JE Jr (2000) Early in vivo experience with tissue-engineered trileaflet heart valves. Circulation 102:III22–III29
Sreekanth MS, Vijayendra SV, Joshi GJ, Shamala TR (2013) Effect of carbon and nitrogen sources on simultaneous production of a-amylase and green food packaging polymer by Bacillus sp. CFR 67. J Food Sci Technol 50:404–408
Steinbüchel A (1991) Polyhydroxyalkanoic acids. In: Byrom D (ed) Biomaterials: novel materials from biological sources. Stockton, New York, pp 124–213
Stock UA, Degenkolbe I, Attmann T, Schenke-Layland K, Freitag S, Lutter G (2006) Prevention of device-related tissue damage during percutaneous deployment of tissue-engineered heart valves. J Thorac Cardiovasc Surg 131:1323–1330
Tang S, Ai Y, Dong Z, Yang Q (1999) Tissue response to subcutaneous implanting poly-3-hydroxybutyrate in rats. Disi Junyi Daxue Xuebao 20:87–89
Tezcaner A, Bugra K, Hasirci V (2003) Retinal pigment epithelium cell culture on surface modified poly(hydroxybutyrate-co-hydroxyvalerate) thin films. Biomaterials 24:4573–4583
Tokiwa Y, Calabia BP (2004) Degradation of microbial polyesters. Biotechnol Lett 26:1181–1189
Turesin F, Gursel I, Hasirci V (2001) Biodegradable polyhydroxyalkanoate implants for osteomyelitis therapy: in vitro antibiotic release. J Biomater Sci Polym Edn 12:195–207
Ueda H, Tabata Y (2003) Polyhydroxyalkanonate derivatives in current clinical applications and trials. Adv Drug Deliv Rev 55:501–518
Urtuvia V, Villegas P, González M, Seeger M (2014) Bacterial production of the biodegradable plastics polyhydroxyalkanoates. Int J Biol Macromol 70:208–213
US Department of Health and Human Services, FDA (1997) Guidance for industry. Rockville, p 54
Valappil SP, Misra SK, Boccaccini AR, Roy I (2006) Biomedical applications of polyhydroxyalkanoates: an overview of animal testing and in vivo responses. Expert Rev Med Devices 3:853–868
Vieyra H, Juárez E, López UF, Morales AG, Torres M (2018) Cytotoxicity and biocompatibility of biomaterials based in polyhydroxybutyrate reinforced with cellulose nanowhiskers determined in human peripheral leukocytes. Biomed Mater 13:045011
Volova T, Goncharov D, Sukovatyi A, Shabanov A, Nikolaeva E, Shishatskaya E (2013) Electrospinning of polyhydroxyalkanoate fibrous scaffolds: effects on electrospinning parameters on structure and properties. J Biomater Sci Polym Edn 25:370–393
Volova TG, Shishatskaya EI, Nikolaeva ED, Sinskey A (2014) In vivo study of 2D PHA matrices of different chemical compositions: tissue reactions and biodegradations. J Mater Sci Technol 30:549–557
Wang YW, Wu Q, Chen GQ (2003) Reduced mouse fibroblast cell growth by increased hydrophilicity of microbial polyhydroxyalkanoates via hyaluronan coating. Biomaterials 24:4621–4629
Wang YW, Wu Q, Chen GQ (2004) Attachment, proliferation and differentiation of osteoblasts on random biopolyester poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds. Biomaterials 25:669–675
Wang YW, Yang F, Wu Q, Cheng YC, Yu PHF, Chen J, Chen GQ (2005) Effect of composition of poly(3-hydroxybutyrate-co-3hydroxyhexanoate) on growth of fibroblast and osteoblast. Biomaterials 26:755–761
Wang B, Pugh S, Nielsen DR, Zhang W, Meldrum DR (2013a) Engineering cyanobacteria for photosynthetic production of 3-hydroxybutyrate directly from CO2. Metab Eng 16:68–77
Wang Y, Jiang XL, Peng SW, Guo XY, Shang GG, Chen JC, Wu Q, Chen GQ (2013b) Induced apoptosis of osteoblasts proliferating on polyhydroxyalkanoates. Biomaterials 34:3737–3746
Wang Y, Yin J, Chen GQ (2014) Polyhydroxyalkanoates, challenges and opportunities. Curr Opin Biotechnol 30:59–65
Weber B, Scherman J, Emmert MY, Gruenenfelder J, Verbeek R, Bracher M, Black M, Kortsmit J, Franz T, Schoenauer R, Baumgartner L, Brokopp C, Agarkova I, Wolint P, Zund G, Falk V, Zilla P, Hoerstrup SP (2011) Injectable living marrow stromal cell-based autologous tissue engineered heart valves: first experiences with a one-step intervention in primates. Eur Heart J 32:2830–2840
Wei X, Hu YJ, Xie WP, Lin RL, Chen GQ (2009) Influence of poly(3hydroxybutyrate-co-4-hydroxybutyrate-co-3-hydroxyhexanoate) on growth and osteogenic differentiation of human bone marrow derived mesenchymal stem cells. J Biomed Mater Res A 90:894–905
Wei DX, Dao JW, Chen GQ (2018) A micro-ark for cells: highly open porous polyhydroxyalkanoate microspheres as injectable scaffolds for tissue regeneration. Adv Mater 30:e1802273
Williams SF, Martin DP, Horowitz DM, Peoples OP (1999) PHA applications: addressing the price performance issue: I. Tissue engineering. Int J Biol Macromol 25:111–121
Williams SF, Martin DP, Gerngross T, Horowitz DM (2001) Removing endotoxin with an oxidizing agent from polyhydroxyalkanoates produced by fermentation. US Patent No 6245537
Winnacker M, Rieger B (2017) Copolymers of polyhydroxyalkanoates and polyethylene glycols: recent advancements with biological and medical significance. Polym Int 66:497–503
Wu Q, Wang Y, Chen GQ (2009) Medical application of microbial biopolyesters polyhydroxyalkanoates. Artif Cells Blood Substit Immobil Biotechnol 37:1–12
Xu XY, Li XT, Peng SW, Xiao JF, Liu C, Fang G, Chen KC, Chen GQ (2010) The behaviour of neural stem cells on polyhydroxyalkanoate nanofiber scaffolds. Biomaterials 31:3967–3975
Xu M, Qin J, Rao Z, You H, Zhang X, Yang T, Wang X, Xu Z (2016) Effect of Polyhydroxybutyrate (PHB) storage on L-arginine production in recombinant Corynebacterium crenatum using coenzyme regulation. Microb Cell Factories 15:15–26
Xue Q, Liu XB, Lao YH, Wu LP, Wang D, Zuo ZQ, Chen JY, Hou J, Bei YY, Wu XF, Leong KW, Xiang H, Han J (2018) Anti-infective biomaterials with surface-decorated tachyplesin I. Biomaterials 178:351–362
Yan C, Wang Y, Shen XY, Yang G, Jian J, Wang HS, Chen GQ, Wu Q (2011) MicroRNA regulation associated chondrogenesis of mouse MSCs grown on polyhydroxyalkanoates. Biomaterials 32:6435–6444
Yang X, Zhao K, Chen GQ (2002) Effect of surface treatment on the biocompatibility of microbial polyhydroxyalkanoates. Biomaterials 23:1391–1397
Yang Y, De Laporte L, Rives CB, Jang J-H, Lin W-C, Shull KR, Shea LD (2005) Neurotrophin releasing single and multiple lumen nerve conduits. J Control Release 104:433–446
Yang XD, Li HM, Chen M, Zou XH, Zhu LY, Wei CJ, Chen GQ (2010) Enhanced insulin production from murine islet beta cells incubated on poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). J Biomed Mater Res A 92:548–555
Ye H, Zhang K, Kai D, Li Z, Loh XJ (2018) Polyester elastomers for soft tissue engineering. Chem Soc Rev 47:4545–4580
Young RC, Wiberg M, Terenghi G (2002) Poly-3-hydroxybutyrate (PHB): a resorbable conduit for long-gap repair in peripheral nerves. Br J Plast Surg 55:235–240
Yue H, Ling C, Yang T, Chen X, Chen Y, Deng H, Wu Q, Chen J, Chen G-Q (2014) A seawater-based open and continuous process for polyhydroxyalkanoates production by recombinant Halomonas campaniensis LS21 grown in mixed substrates. Biotechnol Biofuels 7:108
Zembouai I, Kaci M, Bruzaud S, Benhamida A, Corre YM, Grohens Y (2013) A study of morphological, thermal, rheological and barrier properties of poly (3-hydroxybutyrate-co-3Hydroxyvalerate)/polylactide blends prepared by melt mixing. Polym Test 32:842–851
Zhang J, Cao Q, Li S, Lu X, Zhao Y, Guan JS, Chen JC, Wu Q, Chen GQ (2013) 3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism. Biomaterials 34:7552–7562
Zhang J, Shishatskaya EI, Volova TG, da Silva LF, Chen GQ (2018) Polyhydroxyalkanoates (PHA) for therapeutic applications. Mater Sci Eng C Mater Biol Appl 86:144–150
Zhao K, Yang X, Chen GQ, Chen JC (2002) Effect of lipase treatment on the biocompatibility of microbial polyhydroxyalkanoates. J Mater Sci-Mater M 13:849–854
Zhao K, Deng Y, Chen JC, Chen GQ (2003a) Polyhydroxyalkanoate (PHA) scaffolds with good mechanical properties and biocompatibility. Biomaterials 24:1041–1045
Zhao K, Deng Y, Chen GQ (2003b) Effects of surface morphology on the biocompatibility of polyhydroxyalkanoates. Biochem Eng J 16:115–123
Zhao Y, Zou B, Shi Z, Wu Q, Chen G-Q (2007) The effect of 3-hydroxybutyrate on the in vitro differentiation of murine osteoblast MC3T3-E1 and in vivo bone formation in ovariectomized rats. Biomaterials 28:3063–3073
Zhao H, Cui Z, Sun X, Turng HL, Peng X (2013) Morphology and properties of injection molded solid and microcellular polylactic acid/polyhydroxybutyrate-valerate (PLA/PHBV) blends. Ind Eng Chem Res 52:2569–2581
Zhou L, Chen Z, Chi W, Yang X, Wang W, Zhang B (2012) Mono-methoxy-poly(3-hydroxybutyrate-co-4-hydroxybutyrate)-graft-hyper-branched polyethylenimine copolymers for siRNA delivery. Biomaterials 33:2334–2344
Zinn M, Witholt B, Egli T (2001) Occurrence, synthesis and medical application of bacterial polyhydroxyalkanoate. Adv Drug Deliv Rev 53:5–21
Zubairi SI, Mantalaris A, Bismarck A, Aizad S (2016) Polyhydroxyalkanoates (PHAs) for tissue engineering applications: biotransformation of palm oil mill effluent (POME) to value-added polymers. J Teknol 78:13–29
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interests.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Singh, A.K., Srivastava, J.K., Chandel, A.K. et al. Biomedical applications of microbially engineered polyhydroxyalkanoates: an insight into recent advances, bottlenecks, and solutions. Appl Microbiol Biotechnol 103, 2007–2032 (2019). https://doi.org/10.1007/s00253-018-09604-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-018-09604-y