Polyhydroxyalkanoates: Current applications in the medical field

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.

Key words： Biopolymers; polyhydroxyalkanoates; biocompatibility; medical implantations

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

References

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

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

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

PMID

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

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

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

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

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

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

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

PMID

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PMID

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

PMID