REVIEW

Polyhydroxyalkanoates: Current applications in the medical field

  • Iftikhar Ali ,
  • Nazia Jamil
Expand
  • Microbiology and Molecular Genetics, University of the Punjab, Quaid-i-Azam Campus, Lahore-54590, Pakistan

Received date: 06 Jan 2016

Accepted date: 04 Feb 2016

Published date: 22 Mar 2016

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Polyhydroxyalkanoates (PHAs) are a class of biopolyesters that are synthesized intracellularly by microorganisms, mainly by different genera of eubacteria. These biopolymers have diverse physical and chemical properties that also classify them as biodegradable in nature and make them compatible to living systems. In the last two decades or so, PHAs have emerged as potential useful materials in the medical field for different applications owing to their unique properties. The lower acidity and bioactivity of PHAs confer them with minimal risk compared to other biopolymers such as poly-lactic acid (PLA) and poly-glycolic acid (PGA). Therefore, the versatility of PHAs in terms of their non-toxic degradation products, biocompatibility, desired surface modifications, wide range of physical and chemical properties, cellular growth support, and attachment without carcinogenic effects have enabled their use as in vivo implants such as sutures, adhesion barriers, and valves to guide tissue repair and in regeneration devices such as cardiovascular patches, articular cartilage repair scaffolds, bone graft substitutes, and nerve guides. Here, we briefly describe some of the most recent innovative research involving the use of PHAs in medical applications. Microbial production of PHAs also provides the opportunity to develop PHAs with more unique monomer compositions economically through metabolic engineering approaches. At present, it is generally established that the PHA monomer composition and surface modifications influence cell responses.PHA synthesis by bacteria does not require the use of a catalyst (used in the synthesis of other polymers), which further promotes the biocompatibility of PHA-derived polymers.

Cite this article

Iftikhar Ali , Nazia Jamil . Polyhydroxyalkanoates: Current applications in the medical field[J]. Frontiers in Biology, 2016 , 11(1) : 19 -27 . DOI: 10.1007/s11515-016-1389-z

Acknowledgement

The authors are grateful to the University of the Punjab, Pakistan and the Higher Education Commission, Pakistan for support of this study..
The authors declare no conflict of interest.
Both authors conceived of the work and agreed on the manuscript contents. The literature review and main manuscript writing were performed by Iftikhar Ali
1
Bao G, Mitragotri S, Tong S (2013). Multifunctional nanoparticles for drug delivery and molecular imaging. Annu Rev Biomed Eng, 15: 253–282

2
Basnett P, ChingK Y, Stolz M , KnowlesJ C , BoccacciniA R ,  SmithC,  LockeI C,Keshavarz T , RoyI (2013). Novel Poly (3-hydroxyoctanoate)/Poly (3-hydroxybutyrate) blends for medical applications. Reactive and Functional Polymers, 73(10):1340–1348

3
Bennett R G (1988). Selection of wound closure materials. J Am Acad Dermatol, 18(4 Pt 1): 619–637

DOI PMID

4
Borkenhagen M, Stoll R C, Neuenschwander P, Suter U W, Aebischer P (1998). In vivo performance of a new biodegradable polyester urethane system used as a nerve guidance channel. Biomaterials, 19(23): 2155–2165

DOI PMID

5
Brigham C J, Sinskey A J (2012). Applications of polyhydroxyalkanoates in the medical industry. Int J Biotechnol Wellness Ind, 1: 52–60

6
Chen G Q, Wu Q (2005). The application of polyhydroxyalkanoates as tissue engineering materials. Biomaterials, 26(33): 6565–6578

DOI PMID

7
Chen Q, Liang S, Thouas G A (2013). Elastomeric biomaterials for tissue engineering. Prog Polym Sci, 38(3-4): 584–671

DOI

8
Chen W, Tong Y W (2012). PHBV microspheres as neural tissue engineering scaffold support neuronal cell growth and axon-dendrite polarization. Acta Biomater, 8(2): 540–548

DOI PMID

9
Chuah J A, 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 Stabil, 98(1): 331–338

DOI

10
Dinjaski N, Fernández-Gutiérrez M, Selvam S, Parra-Ruiz F J, Lehman S M, San Román J, García E, García J L, García A J, Prieto M A (2014). PHACOS, a functionalized bacterial polyester with bactericidal activity against methicillin-resistant Staphylococcus aureus. Biomaterials, 35(1): 14–24

DOI PMID

11
Doi Y, Kitamura S, Abe H (1995). Microbial synthesis and characterization of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Macromolecules, 28(14): 4822–4828

DOI

12
Entholzner E, Mielke L, Pichlmeier R, Weber F, Schneck H (1995). [EEG changes during sedation with gamma-hydroxybutyric acid]. Anaesthesist, 44(5): 345–350

DOI PMID

13
Freier T, Kunze C, Nischan C, Kramer S, Sternberg K, Sass M, Hopt U T, Schmitz K P (2002). In vitro and in vivo degradation studies for development of a biodegradable patch based on poly(3-hydroxybutyrate). Biomaterials, 23(13): 2649–2657

DOI PMID

14
Gardel M, Schwarz U (2010). Cell-substrate interactions. J Phys Condens Matter, 22(19): 190301

DOI PMID

15
Geiger B, Spatz J P, Bershadsky A D (2009). Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol, 10(1): 21–33

DOI PMID

16
Gogolewski S, Jovanovic M, Perren S M, Dillon J G, Hughes M K (1993). Tissue response and in vivo degradation of selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA). J Biomed Mater Res, 27(9): 1135–1148

DOI PMID

17
Hazari A, Johansson-Ruden G, Junemo-Bostrom K, Ljungberg C, Terenghi G, Green C, Wiberg M (1999a) A new resorbable wrap-around implant as an alternative nerve repair technique. Journal of Hand Surgery (British and European Volume) 24: 291–295

18
Hazari A, Wiberg M, Johansson-Rudén 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(8): 653–657

DOI PMID

19
He Y, Hu Z, Ren M, Ding C, Chen P, Gu Q, Wu Q (2013). Evaluation of PHBHHx and PHBV/PLA fibers used as medical sutures. J Mater Sci Mater Med, 25(2): 1–11

DOI PMID

20
Hocking P, Marchessault R (1994). Biopolyesters Chemistry and Technology of BIODEGRADABLE POLymers. Blackie Academic & Professional,48–96

21
Hon L Q, Ganeshan A, Thomas S M, Warakaulle D, Jagdish J, Uberoi R (2009). Vascular closure devices: a comparative overview. Curr Probl Diagn Radiol, 38(1): 33–43

DOI PMID

22
Jones N, Cooper J, Waters R, Williams D (2000). Resorption profile and biological response of calcium phosphate filled PLLA and PHB7V. ASTM Spec Tech Publ, 1396: 69–82

23
Kai D, Loh X J (2014). Polyhydroxyalkanoates: Chemical modifications toward biomedical applications. ACS Sustain Chem& Eng, 2(2): 106–119

DOI

24
Kim H W, Chung C W, Rhee Y H (2005). UV-induced graft copolymerization of monoacrylate-poly(ethylene glycol) onto poly(3-hydroxyoctanoate) to reduce protein adsorption and platelet adhesion. Int J Biol Macromol, 35(1-2): 47–53

DOI PMID

25
Köse G T, Korkusuz F, Korkusuz P, Purali N, Özkul A, Hasırcı V (2003). Bone generation on PHBV matrices: an in vitro study. Biomaterials, 24(27): 4999–5007

DOI PMID

26
Kostopoulos L, Karring T (1994). Guided bone regeneration in mandibular defects in rats using a bioresorbable polymer. Clin Oral Implants Res, 5(2): 66–74

DOI PMID

27
Kunze C, Edgar Bernd H, Androsch R, Nischan C, Freier T, Kramer S, Kramp B, Schmitz K P (2006). In vitro and in vivo studies on blends of isotactic and atactic poly (3-hydroxybutyrate) for development of a dura substitute material. Biomaterials, 27(2): 192–201

DOI PMID

28
Kuroda K, Caputo G A (2013). Antimicrobial polymers as synthetic mimics of host-defense peptides. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 5(1): 49–66

DOI PMID

29
Laycock B, Halley P, Pratt S, Werker A, Lant P (2013). The chemomechanical properties of microbial polyhydroxyalkanoates. Prog Polym Sci, 38(3-4): 536–583

DOI

30
Levine A C, Sparano A, Twigg FF, Numata K, Nomura C T (2015). Influence of cross-linking on the physical properties and cytotoxicity of polyhydroxyalkanoate (PHA) scaffolds for tissue engineering. ACS Biomater Sci Eng, 1(7): 567–576

31
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(4): 985–998

DOI PMID

32
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(3): 1169–1175

DOI PMID

33
Li X T, Sun J, Chen S, Chen G Q (2008). In vitro investigation of maleated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) for its biocompatibility to mouse fibroblast L929 and human microvascular endothelial cells. J Biomed Mater Res A, 87(3): 832–842

DOI PMID

34
Lizarraga-Valderrama L R, Nigmatullin R, Taylor C, Haycock J W, Claeyssens F, Knowles J C, Roy I (2015). Nerve tissue engineering using blends of poly (3-hydroxyalkanoates) for peripheral nerve regeneration. Eng Life Sci, 15(6): 612–621

DOI

35
Lomas A J, Webb W R, Han J, Chen G Q, Sun X, Zhang Z, El Haj A J, Forsyth N R (2013). Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate)/collagen hybrid scaffolds for tissue engineering applications. Tissue Eng Part C Methods, 19(8): 577–585

DOI

36
Lu H X, Yang Z Q, Jiao Q, Wang Y Y, Wang L, Yang P B, Chen X L, Zhang P B, Wang P, Chen M X, Lu X Y, 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(3): 207–214

DOI PMID

37
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(06): 731–740

DOI

38
Luklinska Z B, Bonfield W (1997). Morphology and ultrastructure of the interface between hydroxyapatite-polyhydroxybutyrate composite implant and bone. J Mater Sci Mater Med, 8(6): 379–383

DOI PMID

39
Mauclaire L, Brombacher E, Bünger J D, Zinn M (2010). Factors controlling bacterial attachment and biofilm formation on medium-chain-length polyhydroxyalkanoates (mcl-PHAs). Colloids Surf B Biointerfaces, 76(1): 104–111

DOI PMID

40
McBeath R, Pirone D M, Nelson C M, Bhadriraju K, Chen C S (2004). Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell, 6(4): 483–495

DOI PMID

41
Miller N D, Williams D F (1987). On the biodegradation of poly-beta-hydroxybutyrate (PHB) homopolymer and poly-beta-hydroxybutyrate-hydroxyvalerate copolymers. Biomaterials, 8(2): 129–137

DOI PMID

42
Moy R L, Waldman B, Hein D W (1992). A review of sutures and suturing techniques. J Dermatol Surg Oncol, 18(9): 785–795

DOI PMID

43
Mukai K, Doi Y, Sema Y, Tomita K (1993). Substrate specificities in hydrolysis of polyhydroxyalkanoates by microbial esterases. Biotechnol Lett, 15(6): 601–604

DOI

44
Naveen S V, Tan I K P, Goh Y S, Raghavendran H R B, Murali M R, Kamarul T (2015). Unmodified medium chain length polyhydroxyalkanoate (uMCL-PHA) as a thin film for tissue engineering application–characterization and in vitro biocompatibility. Mater Lett, 141: 55–58

DOI

45
Nelson T, Kaufman E, Kline J, Sokoloff L (1981). The extraneural distribution of g-hydroxybutyrate. J Neurochem, 37(5): 1345–1348

DOI PMID

46
Novikov L N, Novikova L N, Mosahebi A, Wiberg M, Terenghi G, Kellerth J O (2002). A novel biodegradable implant for neuronal rescue and regeneration after spinal cord injury. Biomaterials, 23(16): 3369–3376

DOI PMID

47
Novikova L N, Pettersson J, Brohlin M, Wiberg M, Novikov L N (2008). Biodegradable poly-beta-hydroxybutyrate scaffold seeded with Schwann cells to promote spinal cord repair. Biomaterials, 29(9): 1198–1206

DOI PMID

48
O’Connor S, Szwej E, Nikodinovic-Runic J, O’Connor A, Byrne A T, Devocelle M, O’Donovan N, Gallagher W M, Babu R, Kenny S T, Zinn M, Zulian Q R, O’Connor K E (2013). The anti-cancer activity of a cationic anti-microbial peptide derived from monomers of polyhydroxyalkanoate. Biomaterials, 34(11): 2710–2718

DOI PMID

49
Pawan G L, Semple S J (1983). Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation. Lancet, 1(8314-5): 15–17

DOI PMID

50
Pelham R J Jr, Wang Y (1997). Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc Natl Acad Sci USA, 94(25): 13661–13665

DOI PMID

51
Peng S W, Guo X Y, Shang G G, Li J, Xu X Y, You M L, Li P, Chen G Q (2011). An assessment of the risks of carcinogenicity associated with polyhydroxyalkanoates through an analysis of DNA aneuploid and telomerase activity. Biomaterials, 32(10): 2546–2555

DOI PMID

52
Philip S, Keshavarz T, Roy I (2007). Polyhydroxyalkanoates: biodegradable polymers with a range of applications. J Chem Technol Biotechnol, 82(3): 233–247

DOI

53
Qu X H, Wu Q, Liang J, Qu X, Wang S G, Chen G Q (2005). Enhanced vascular-related cellular affinity on surface modified copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx). Biomaterials, 26(34): 6991–7001

DOI PMID

54
Qu X H, Wu Q, Zhang K Y, Chen G Q (2006). In vivo studies of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) based polymers: biodegradation and tissue reactions. Biomaterials, 27(19): 3540–3548

DOI PMID

55
Ricotti L, Polini A, Genchi G G, 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(3): 035010

DOI PMID

56
Saito T, Tomita K, Juni K, Ooba K (1991). In vivo and in vitro degradation of poly(3-hydroxybutyrate) in rat. Biomaterials, 12(3): 309–312

DOI PMID

57
Shangguan Y Y, Wang Y W, Wu Q, Chen G Q (2006). The mechanical properties and in vitro biodegradation and biocompatibility of UV-treated poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). Biomaterials, 27(11): 2349–2357

DOI PMID

58
Shen F, Zhang E, Wei Z (2009). Surface bio-modification of poly(hydroxybutyrate-co-hydroxyhexanoate) and its aging effect. Colloids Surf B Biointerfaces, 73(2): 302–307

DOI PMID

59
Shishatskaya E I, Volova T G, Gordeev S A, Puzyr A P (2005). Degradation of P(3HB) and P(3HB-co-3HV) in biological media. J Biomater Sci Polym Ed, 16(5): 643–657

DOI PMID

60
Shrivastav A, Kim H Y, Kim Y R (2013). Advances in the applications of polyhydroxyalkanoate nanoparticles for novel drug delivery system. BioMed Res Int, 2013: 581684

DOI PMID

61
Sodian R, Hoerstrup S P, Sperling J S, Daebritz S, Martin D P, Moran A M, Kim B S, Schoen F J, Vacanti J P, Mayer J E Jr (2000). Early in vivo experience with tissue-engineered trileaflet heart valves. Circulation, 102(19 Suppl 3): III22–III29

PMID

62
Stock U A, 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(6): 1323–1330

DOI PMID

63
Sun J, Dai Z, Zhao Y, Chen G-Q (2007). In vitro effect of oligo-hydroxyalkanoates on the growth of mouse fibroblast cell line L929. Biomaterials, 28: 3896–3903

64
Taylor M S, Daniels A U, Andriano K P, Heller J (1994). Six bioabsorbable polymers: in vitro acute toxicity of accumulated degradation products. J Appl Biomater, 5(2): 151–157

DOI PMID

65
Tezcaner A, Bugra K, Hasırcı V (2003). Retinal pigment epithelium cell culture on surface modified poly(hydroxybutyrate-co-hydroxyvalerate) thin films. Biomaterials, 24(25): 4573–4583

DOI PMID

66
Valappil S P, Misra S K, Boccaccini A R, Roy I (2006). Biomedical applications of polyhydroxyalkanoates: an overview of animal testing and in vivo responses. Expert Rev Med Devices, 3(6): 853–868

DOI PMID

67
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 Ed, 25(4): 370–393

PMID

68
Wang Y, Jiang X L, Peng S W, Guo X Y, Shang G G, Chen J C, Wu Q, Chen G Q (2013). Induced apoptosis of osteoblasts proliferating on polyhydroxyalkanoates. Biomaterials, 34(15): 3737–3746

DOI PMID

69
Wang Y, Jiang X L, Yang S C, Lin X, He Y, Yan C, Wu L, Chen G Q, Wang Z Y, Wu Q (2011). MicroRNAs in the regulation of interfacial behaviors of MSCs cultured on microgrooved surface pattern. Biomaterials, 32(35): 9207–9217

DOI PMID

70
Wang Y W, Wu Q, Chen G Q (2004). Attachment, proliferation and differentiation of osteoblasts on random biopolyester poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds. Biomaterials, 25(4): 669–675

DOI PMID

71
Wang Y W, Wu Q, Chen G Q (2005). Gelatin blending improves the performance of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) films for biomedical application. Biomacromolecules, 6(2): 566–571

DOI PMID

72
Wei X, Hu Y J, Xie W P, Lin R L, Chen G Q (2009). Influence of poly(3-hydroxybutyrate-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(3): 894–905

DOI PMID

73
Wu Q, Wang Y, Chen G Q (2009). Medical application of microbial biopolyesters polyhydroxyalkanoates Artificial Cells. Blood Substitutes and Biotechnology, 37(1): 1–12

DOI

74
Xu X Y, Li X T, Peng S W, Xiao J F, Liu C, Fang G, Chen K C, Chen G Q (2010). The behaviour of neural stem cells on polyhydroxyalkanoate nanofiber scaffolds. Biomaterials, 31(14): 3967–3975

DOI PMID

75
Yan C, Wang Y, Shen X Y, Yang G, Jian J, Wang H S, Chen G Q, Wu Q (2011). MicroRNA regulation associated chondrogenesis of mouse MSCs grown on polyhydroxyalkanoates. Biomaterials, 32(27): 6435–6444

DOI PMID

76
Yang X, Zhao K, Chen G Q (2002). Effect of surface treatment on the biocompatibility of microbial polyhydroxyalkanoates. Biomaterials, 23(5): 1391–1397

DOI PMID

77
Yu B Y, Chen C R, Sun Y M, Young T H (2009). The response of rat cerebellar granule neurons (rCGNs) to various polyhydroxyalkanoate (PHA) films. Desalination, 245(1-3): 639–646

DOI

78
Zhao K, Deng Y, Chun Chen J, Chen G Q (2003). Polyhydroxyalkanoate (PHA) scaffolds with good mechanical properties and biocompatibility. Biomaterials, 24(6): 1041–1045

DOI PMID

79
Zhao K, Yang X, Chen G Q, Chen J C (2002). Effect of lipase treatment on the biocompatibility of microbial polyhydroxyalkanoates. J Mater Sci Mater Med, 13(9): 849–854

DOI PMID

80
Zhao Q, Wang S, Kong M, Geng W, Li R K, Song C, Kong D (2012). Phase morphology, physical properties, and biodegradation behavior of novel PLA/PHBHHx blends. J Biomed Mater Res B Appl Biomater, 100(1): 23–31

DOI PMID

81
Zink D, Fischer A H, Nickerson J A (2004). Nuclear structure in cancer cells. Nat Rev Cancer, 4(9): 677–687

DOI PMID

Outlines

/