Medical Application of Microbial Biopolyesters Polyhydroxyalkanoates

Figures & data

Figure 1.  General molecular structure of polyhydroxyalkanoates (Chen & Wu 2005). _x=1, 2, 3, yet x = 1 is most common, n can range from 100 to several thousands. R is variable. When x = 1, R = CH₃, the monomer structure is 3-hydroxybutyrate, while x = 1 and R = C₃H₇, it is a 3-hydroxyhexanoate monomer.

Table 1. Comparison of polymer properties (Khanna & Srivastava, 2005)

Polymer	Melting point (°C)	Young's modulus (GPa)	Tensile strength (MPa)	Elongation to break (%)	Glass transition temperature (°C)
P(3HB)	179	3.5	40	5	4
P(3HB-co-3HV)
3mol% 3HV	170	2.9	38	–	–
9mol% 3HV	162	1.9	37	–	–
14mol% 3HV	150	1.5	35	–	–
20mol% 3HV	145	1.2	32	–	–
25mol% 3HV	137	0.7	30	–	–
P(3HB-co-4HB)
3mol% 4HB	166	–	28	45	–
10mol% 4HB	159	–	24	242	–
16mol% 4HB	–	–	26	444	–
64mol% 4HB	50	30	17	591	–
90mol% 4HB	50	100	65	1080	–
P(4HB)	53	149	104	1000	–
P(3HHx-co-3HO)	61	–	10	300	–
P(3HB-co-6mol% 3HA)	133	0.2	17	680	−8
P(3HB-co-67mol% HP)	44	–	–	–	−19
P(3HB-co-3HHx)	52	–	20	850	−4
Polypropylene	170	1.7	34.5	400	45
Polyethylene-terepthalate	262	2.2	56	7300	3400
Polystyrene	110	3.1	50	–	21
LDPE	130	0.2	10	620	−30

Figure 2.  Various applications of PHA in medical fields. (A) Artificial esophagus; (B) Vascular patches; (C) Nerve conduit tissue engineering; (D) Articular cartilage tissue engineering; (E) Nutritional and therapeutic uses by oral administration.

Table 2. Patents for medical application of polyhydroxyalkanoates since 2000

Patent (year)	Contents
WO2007090255 (2007)	Polymeric implant for controlling the release of progestogens (Nascimento & Pachekoski, 2008)
US2007185561 (2007)	Stent useful in e.g. coronary and esophageal procedure (Schmitz et al., 2007)
WO2007009090 (2007)	Hemostatic agent for treating intracavity bleeding (Huja et al., 2007)
US2007182041 (2007)	Shaped object such as suture fasteners (Rizk et al., 2007)
WO2006068421 (2006)	Porous mesh (Bae et al., 2006)
WO2005020825 (2005)	Nerve regeneration device (Terenghi, Mohanna, & Martin, 2005)
US2005058724 (2005)	Fluid therapy used for treating metabolic acidosis and in dialysis (e.g. hemodialysis) therapy (Veech, 2005)
WO2005020825 (2005)	Nerve regeneration device (Terenghi, Mohanna, & Martin, 2005)
WO2004096188 (2004)	Structure useful in microcapsule for delivery of drug (Yano et al., 2004)
WO2004097417 (2004)	Construct useful as functional composite construct (Imamura et al., 2004)
WO2004097416 (2004)	Magnetic substance-bio-substance complex structure (Imamura et al., 2004)
WO2004108740 (2004)	Nutritional and therapeutic uses of (R)-3-hydroxybutyrate (Veech et al., 2004)
WO2004101002 (2004)	P(4HB) fiber useful in devices such as medical textile, tube, general surgical mesh, hernia mesh, pericardial patch, anti-adhesion patch (Martin et al., 2004)
EP1277464 (2003)	Polyhydroxyalkanoate-coated liposome useful as medicinal substance, e.g. tissue-oriented drug delivery agent (Nomoto et al., 2003)
EP1275378 (2003)	Particulate construct, useful for slow release of, e.g., drugs or ultrasonic contrast agents (Yano et al., 2003)
EP1332173 (2002)	Disposal of biodegradable material, e.g. medical tubing (Noda, 2002)
EP1132446 (2002)	Adhesive dispersion for forming non-woven materials used for disposable sanitary articles (Noda, 2002)
WO200119422 (2001)	Repair of soft tissue (Williams et al., 2001)
WO200115671 (2001)	Drug delivery devices or bandages (Williams, 2001)
WO200119361 (2001)	Nutritional and therapeutic composition comprising polymers and oligomers of gamma-hydroxybutyrate (Williams et al., 2001)
WO200056376 (2000)	Sutures, tissue repair devices, bone grafts and wound dressings (Williams et al., 2000)
WO200051662 (2000)	Biocompatible, bioabsorbable polymers with mechanical properties that provide a better match with those of tissue structures (Williams, 2000)
CA2247013 (2000)	Microencapsulation or entrapment of hydrophilic or lipophilic drugs (Marchessault, Nobes, & Maysinger, 2000)
WO200015216 (2000)	Nutritional and therapeutic cyclic esters of (R)-3-hydroxybutyrate (Veech, 2000)
WO200004895 (2000)	Nutritional and therapeutic compositions comprise oligomers or esters of 3-hydroxyacids (Martin et al., 2000)

Figure 3.  Fibronectin (green) distribution and actin filament formation (red) in SMCs cultured on test films(Qu et al. 2005). (A) SMCs cultured on PHBHHx stained with anti-fibronectin revealed an intense, granular and an oriented delicate fibrillar extracellular labeling pattern. Fibronectin was co-localized with actin filaments clearly (arrow). (B) SMCs on P-PHBHHx stained with anti-fibronectin revealed an intense, perinuclear, granular labeling pattern. Fibronectin was co-localized with actin filaments obviously (arrow). (C) SMCs on Fn-PHBHHx stained with anti-fibronectin revealed a random granular labeling pattern. Fibronectin revealed almost no co-localization with actin filaments (arrow). (D) SMCs cultured on PFn-PHBHHx stained with anti-fibronectin revealed a tense, granular, perinuclear labeling pattern. The co-localization between fibronectin and actin was impaired in some cells (blue arrow) while normal in others (white arrow). (A) PHBHHx; (B) P-PHBHHx; (C) Fn-PHBHHx; (D) PFn-PHBHHx (confocal microscopy, LSM510 meta, Zeiss).

Figure 4.  Glial cell apoptosis study by Annexin V-FITC staining assay (Xiao, Zhao, & Chen 2007). Glial cells at an initial concentration of 10⁵ cells/well were grown in DMEM medium supplemented with 20% FBS for 24 h. After the cells attached on the bottom of the wells, the culture medium was replaced by DMEM medium. D-3-HB, DL-3-HB and M-3-HB were all added in 10 mM to the culture medium, respectively. After 48 h, the cells were harvested and stained by Annexin V-FITC and PI. The dead cells were stained by PI and the cells in apotosis were stained by Annexin V-FITC and allocated in the D4 region. (A)—(a) control: cells cultured with DMEM medium; (b) cells cultured with DMEM supplemented with 10mM D-3-HB; (c) cells cultured with DMEM supplemented with 10mM DL-3-HB; (d) cells cultured with DMEM supplemented with 10mM M-3-HB. (B) The percentage of cell apoptosis: statistic result obtained by averaging 6 flow cytometry results of each group in (A).