The Clinical Future of Polyhydroxyalkanoates

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Polyhydroxyalkanoates (PHAs) have long been known to scientists, but due to high costs and low market demand, they have not yet been successfully commercialized. PHAs are a group of biodegradable polymer produced by bacterial cells in the same way humans produce fat. Recently, they have been suggested as being appropriate for a number of medical applications, such as sutures and tissue engineering due to their high biocompatibility with the human body. Along with sutures and tissue grafts, PHAs have been suggested as a vehicle for controlled release drug delivery as the different types of PHA mean that the properties and degradation rates can be manipulated to suit a particular purpose. While little research has been done into the field of drug synthesis with respect to PHAs, it is suggested that drug synthesis using PHAs be explored since the optical purity of PHAs would allow for a more effective drug. Some PHAs also have therapeutic properties and could be used as a drug to treat a range of mental illnesses.

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The emerging field of polyhydroxyalkanoates (PHAs) has a vast range of potential applications. While today’s environmentally conscious world is continually searching for environmentally friendly alternatives to petrochemicals for applications such as packaging, office supplies, and household uses (1), novel applications that can be tailored to PHAs are often be overlooked. In the past decade, PHAs have been proposed as a highly useful tool for the medical field due to their biocompatibility and biodegradability. While some of these clinical uses are still in our future, companies in the United States and Japan have already begun pilot plant studies and are undertaking research into PHA based tissue engineering and implants (1, 2). There are a wide range of PHA monomers, such as 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV) (3). These monomers can also be bonded to one another, to create copolymers such as poly(3hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) (3) [Figure 1].

FIG. 1 | 3HB and 3HV Monomers and PHBV Unit

FIG. 1 | 3HB and 3HV Monomers and PHBV Unit

PHA technology is commonly cited as a future for medical applications such as dissolvable sutures and skin grafts (4). PHAs also have potential to act as a carrier for drugs to help target certain parts of the body or to delay the release of a drug into the body. Finally, while the technology may be several years away, due to certain unique properties of PHA formation, PHAs could be used as an alternative, more efficient, drug synthesis mechanism. Due to the unique properties of PHA polymers, such as their biocompatibility, optical purity, and rate of biodegradation, PHA technology has the potential to surpass existing technologies in the future and become a benchmark in the fields of bioengineering and

Sutures and Tissue Engineering

One of the most commonly proposed clinical applications for PHAs is use as sutures or skin grafts (4). PHAs are able to biodegrade in a very wide range of conditions, including in seawater and the human body (2). Because of this property, PHAs have been proposed as an effective dissolvable suture. According to Bhubalan, Lee (5), intramuscular sutures made from P(3HB) and P(3HB-co-15 mol% 3HV) were found to be of comparable strength to traditional silk and catgut sutures. The PHA sutures were of sufficient strength across the full healing time of a muscular facial wound in rats. No significant adverse effects were observed in the study (5). As sutures are required to be moderately elastic, P(3HBco-3HV) would be the better polymer to use from these two since PHBV copolymers have a greater elongation to break than PHB homopolymers (6). The more expensive polyhydroxyhexanoate (PHHx) would also be suitable for suture applications as it also has a high elasticity (5). Due to the way they biodegrade in the body, PHAs have also been suggested as scaffolds for skin grafts and tissue engineering (1). Biocompatibility is a complex concept, as the original materials, degradation rates, and degraded materials must all be considered. Kok and Hasirci (3) reported that PHB and PHV, the two most common types of PHA, are highly biocompatible, with very few adverse effects being exhibited when implanted in rabbit tissue. Other tests using rabbits and sheep have shown that P(4HB) and the less common P(3HB-co-3HHx) and P(3HO-co-3HHx) copolymers are also suitable as tissue scaffolds, especially in the circulatory system (5). In 1995, a Swedish team successfully used P(3HB) as a tissue scaffold in human patients following cardiovascular surgery (7). The team found that the P(3HB) patches lowered the rate of postoperative adhesion and that the patch was successfully biodegrading in the body after a period of 6-24 months (7).

PHA production is currently more expensive than the production of the conventional petrochemical plastics that are currently being used. However, recent advances in lowering the costs of common PHAs (8) have turned this application into a very feasible one. For clinical applications, cost is often less important than the performance of the material, making it an ideal stepping stone for PHA production to develop as an industry.

Purity of the polymer is a barrier in clinical applications in general. To date, it is very difficult to purify PHAs enough to gain regulatory approval for use in most clinical applications (3, 9). Unfortunately, there is, as of yet, no official standard for PHA purity set by medical regulatory bodies, so researchers do not have a target purity to aim for. Some studies involving clinical trials of tissue grafts have been approved, but others have been rejected on the basis of purity (5). There are a number of ways to purify PHA polymers, each of which achieves a varying level of purity. Each method also has other practical considerations such as cost, yield, and industrial scale up prospects, which have been summarized by Koller, Niebelshutz & Braunegg. Based on their findings, alkaline digestion appears to be the most promising and commercially viable method to purify PHAs to a medical grade. This method gives a high purity, while keeping costs down and remaining viable for industrial scale-ups (10). It is clear that high purity and potential for industrial scale-ups rarely coincide, so it will be necessary for the appropriate regulatory boards to set a standard for purity before a purification method is decided upon. Unfortunately, the alkaline digestion method does not work for all bacterial strains (10), so this cannot be performed on cheaper, mixed culture production methods.

Drug Delivery

Some work has also been done in the field of PHAs as a drug delivery method (1). PHAs, like most biodegradable polymers, are broken down via a mechanism known as chain cleavage. This is where a long polymeric chain is broken down into smaller chains, and then eventually into individual monomers. In the case of PHAs, chain cleavage is cause by microorganisms secreting depolymerase, a chemical which is naturally produced in bacteria to break down PHAs for consumption during times of famine. There are two main types of degradation patterns for biodegradable polymers in general, bulk erosion and surface erosion (11). PHAs only exhibit surface erosion (5), which is where the polymer degrades from the outside. This erosion pattern has been suggested as the better pattern for use in controlled or targeted drug delivery devices. The rate of surface erosion is dependent on surface area and thickness of the polymer (11), which allows manipulation of release times to be fairly simple. PHAs degrade in aerobic environments to produce carbon dioxide and water, with the addition of methane in anaerobic environments (5).

One of the biggest opportunities in the field of PHA drug delivery is delayed, or controlled release, drugs. PHA degradation in the body is slower than the degradation of more commonly used drug delivery matrices, such as poly(lactide-co-glycolide), and can be altered based on the molecular weight of the polymer (3). One of the biggest problems with anticancer drugs is their propensity to kill tumor tissue at the expense of contaminating the entire body. Vauthier, Fattal (12) proposed one method to combat this problem, which is the use of nanoparticles. However, PHAs may be another alternative. Due to their slow degradation rate, PHA encapsulated drugs would not wreak havoc on the body on their way to the targeted tumor tissue. Work is being done to develop highly specific cancer targeting drugs (13), so PHA encapsulated drugs could travel through the body towards the tumor without degrading and contaminating the body.

Another opportunity in PHA drug delivery is controlled release systems to achieve a certain drug concentration in the body over a period of time (5).This would be highly beneficial to Type I diabetics, as it would allow a single injection every day, rather than regular injections after sugar consumption. Previous studies have shown that release rates can be controlled by drug concentration and PHA molecular weight (5). This would allow for tailoring of drug release rates depending on the patient’s individual needs. Some of this technology is already being developed and patented. Using a combination of P(3HB) and polylactic acid (PLA), another biodegradable polymer, a controlled release drug capsule containing celiprolol, a blood pressure regulator. It was proven that altering the ratios of celiprolol to PLA to P(3HB) could alter the release rate of the drug into the body (14). In 2005, Metabolic Inc. also successfully applied for a patent in this field. Researchers had found that incorporating 2- hydroxyacids, which are smaller than PHA monomers, could speed up degradation by making the polymer chain more susceptible to enzymatic attack (15).

A Novel Idea: Drug Synthesis

A particularly unique property exhibited by PHAs is their optical purity. Several studies have observed that only the R enantiomer of a PHA will form (16). While it is not considered an important property for many present uses, this property can open the door to a brand new clinical application for PHAs: drug synthesis.

One of the biggest problems for the pharmaceutics industry is the presence of different enantiomers, or optical isomers. While different enantiomers have identical physical and thermal properties, they can be identified by their rotation in polarized light. Different enantiomers also react differently with other chiral molecules, such as those found in our bodies (17). This concept was the cause of the thalidomide tragedy during the late 1950s and early 1960s. One enantiomer of the drug was highly effective in curing morning sickness, while the other enantiomer was later found to cause severe birth defects. Following the withdrawal of thalidomide from the market, tougher legislation was introduced to prevent another similar situation from happening in the future (18). Currently, extensive tests are done to isolate enantiomers and test them individually to ensure there are no adverse effects from the inactive enantiomer (17).

In addition to their optical purity, the type of PHA formed is dependent on the feeding substrate that is provided and the strain of bacteria (19), which results in over 150 different PHAs having been observed and even more having been postulated (2). Sudesh & Doi further explain that bacteria from the genus Pseudomonads are particularly versatile and can produce a wide range of branched, aromatic, and even halogenated PHAs containing 6-14 carbon atoms (2005).

While 6-14 carbon atoms do not seem to be large numbers, several common drugs, most notably the painkiller and muscle relaxant, ibuprofen (Figure 2), contain a number of carbon atoms within this range. Significantly, the R enantiomer of ibuprofen is the active enantiomer, hence it may be possible to synthesize an optically pure form of ibuprofen as a PHA from bacteria (Figure 3).While producing ibuprofen in this way may be expensive, it may appeal to pharmaceutical companies due to its lesser waste and the simplicity of the process. The more commonly used Boot’s synthesis is a process which requires several steps (20) (Figure 4). The multi-step process can drive production costs up, as numerous reaction vessels may be required.

FIG. 2 | Synthesis pathway of PHB from glucose.

FIG. 2 | Synthesis pathway of PHB from glucose.

FIG. 3 | Ibuprofen Molecule with R-Configuration Highlighted

FIG. 3 | Ibuprofen Molecule with R-Configuration Highlighted

FIG. 4 | Boots Synthesis of Ibuprofen showing waste products

FIG. 4 | Boots Synthesis of Ibuprofen showing waste products

The Boot’s synthesis also produces a number of waste products, which, while largely harmless, are a concern for production companies, as a disposal procedure must be considered. Furthermore, an optically pure drug would mean that half of the active ingredient is necessary for an effective drug, hence capsules or tablets could be smaller. When developing new drugs, pharmaceutical companies can also save time and money in research and regulatory approval as only one enantiomer will need to be tested and approved.

It has also been observed that some moderately common PHAs, such as P(3HB-co-4HB) and P(4HB), have some useful therapeutic properties. 4HB units (Figure 5) are known to be an anesthetic that can affect the brain quickly without disturbing other systems in the body (5). Less common is the knowledge that 4HB units have been observed to be effective at treating psychological disorders, such as schizophrenia, narcolepsy, and drug and alcohol withdrawal. These polymers are commonly found in mammalian brain cells (2), though little is understood about the mechanism by which 4HB units can resolve or prevent such psychological disorders. It is recommended that this interaction be studied more in-depth to further explore the possibilities for using 4HB units as treatment for these disorders.

FIG. 5 | 4HB Monomer

FIG. 5 | 4HB Monomer

Conclusions and Recommendations

PHAs are a hugely versatile material that has enormous potential for use in the medical market. While purification is currently a problem, dissolvable sutures and tissue graft scaffolds have the potential to surpass existing technologies, such as silk or catgut, because of their exceptional biocompatibility. Some clinical trials have already been undertaken, which have shown that P(3HB) patches are superior to traditional technologies, but it is recommended that a standard be set for medical grade PHA so researchers can better develop the technology. Using PHA as capsules or microcapsules for controlled or delayed release drug treatments is also being explored. PHA capsules or microcapsules can protect the body from harmful side effects of drugs such as chemotherapy drugs by delaying the release of the drug. They can also help maintain constant levels of a drug in the body, such as insulin for Type I diabetics. While little has been seriously considered in the area of drug synthesis, PHAs can provide a novel method for producing drugs. The optical purity of PHAs can allow pharmaceutical companies to save huge amounts of money and time, as they won’t have to isolate and test two different enantiomers when developing new drugs. It can also save money producing existing drugs as less waste will be produced and less active ingredients will need to be synthesized. Some therapeutic effects have also been observed in 4HB units, found naturally in mammalian brains, such as the ability to prevent psychological disorders such as schizophrenia and drug and alcohol withdrawal. Little is known about the mechanism by which 4HB units affect the brain’s chemistry, so it is recommended that further research be conducted to understand what the units do and how they can be used commercially to treat mental illness.

[fusion_old_tabby title=”Figures”] [fusion_old_tabby title=”References”]
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