Polyhydroxyalkanoates: Current applications in the medical field
Received date: 06 Jan 2016
Accepted date: 04 Feb 2016
Published date: 22 Mar 2016
Copyright
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.
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
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
|
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
|
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
|
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
|
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
|
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
|
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
|
14 |
Gardel M, Schwarz U (2010). Cell-substrate interactions. J Phys Condens Matter, 22(19): 190301
|
15 |
Geiger B, Spatz J P, Bershadsky A D (2009). Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol, 10(1): 21–33
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
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
|
76 |
Yang X, Zhao K, Chen G Q (2002). Effect of surface treatment on the biocompatibility of microbial polyhydroxyalkanoates. Biomaterials, 23(5): 1391–1397
|
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
|
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
|
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
|
81 |
Zink D, Fischer A H, Nickerson J A (2004). Nuclear structure in cancer cells. Nat Rev Cancer, 4(9): 677–687
|
/
〈 | 〉 |