Issue 18/2012 - Discussion on the biocompatibility of modified polylactic acid

Polylactic acid (PLA) is an aliphatic polyester compound, which is non-toxic, non-irritating, biodegradable and good biocompatibility, and can be completely degraded by microorganisms under natural conditions, and finally produces carbon dioxide and water, which is an environmentally friendly material
.
Polylactic acid has a promising application in the fields of medicine and biology, but its wide application
in medical treatment is limited due to its hydrophobicity and physical brittleness.
Therefore, many people in the material industry have improved polylactic acid, hoping to obtain new medical polymer materials
with certain toughness and bearing capacity, and at the same time have good degradation and biocompatibility of polylactic acid.
As a result, polymer materials
such as polyglycolic acid (PGA), lactic acid-glycolic acid copolymer (PLGA), and L-polylactic acid (PLLA) have emerged.

1.
Evaluation of blood compatibility and cell compatibility

The hemolysis process is the process in
which red blood cells are stimulated to rupture and release hemoglobin into the surrounding solution.
The School of Materials Science of Fudan University uses fresh rabbit blood as an experimental material for hemocompatibility experiments
.
Studies have shown that L-polylactic acid (PLLA) has a hemolysis rate of less than 5%, indicating that the material has good blood compatibility
.
Platelet adhesion experiments with rabbit blood as material showed that polylactic acid and its copolymers were not suitable for antiplatelet drug carriers
.
In the cytocompatibility experiment using rabbit blood cells, the cells were adhered to polymer L-lactic acid (PLLA), L-lactic acid-trimethyl carbonate copolymer (PLLA-TMC), racemic polylactic acid-trimethyl carbonate copolymer (PDLLA-TMC) films, and observed their growth after a period of culture, and found that there was no significant difference between
all experimental groups and control groups.
Therefore, it can be seen that polylactic acid has good cytocompatibility
.

Second, the influence of the physical and chemical properties of polylactic acid and its polymers on biocompatibility

1.
The influence of the shape of
the material polylactic acid is often used as a slow-release preparation, the material will exist in the organism for a long time, and its shape also has a great impact on the body, such as smooth material cells are not easy to attach, can reduce the inflammatory response
.
At the same time, if the shape continues to stimulate a part of the body, it will lead to aseptic inflammation
.
In addition, the different sizes of the materials also have a very different effect
on the effects of the polylactic acid material in the body.
Anderson et al.
of Case Western Reserve University in the United States summarized the biocompatibility and biodegradability of PLA and PLGA (copolymer of hydroxyacetic acid and lactic acid), and compared with larger implants, the microspheres have a larger contact area with the body, and it can be observed that each microsphere surface is surrounded by
inflammatory cells and foreign body giant cells.
The fibrous sac surrounds the entire implant site, while collagen and new capillaries may be visible in the spheroid space
.

2.
The influence of polymer polymerization degree on molecular weight will affect the biocompatibility of polylactic acid from two aspects: first, the faster decomposition of polymers with low molecular weight leads to the release of a large amount of
polylactic acid, making the local acidity too high, thereby aggravating the inflammatory response; Second, the degree of polymerization of polylactic acid affects the overall structure of the material, thereby affecting the release rate
of the encapsulated drug.
When polymers are used as drug carrier systems, the general drug release process enters a relatively gentle release process
after sudden release.
Zhang et al.
of Fudan University used thymus pentapeptide (TP5) as a model drug to study the release process of PLA-PEG-PLA as a drug carrier, and found that the polymer drug carrier with larger molecular weight had a smaller burst release concentration and a slower drug release rate
.

3.
The influence
block copolymer produced by the introduction of modified products refers to a special polymer prepared by joining two or more polymer
segments together.
ABA triblock copolymer compound is a polymer structure
formed by polymer chains connected on both sides of another polymer chain.
Triblock copolymers are introduced to overcome some of the biocompatibility shortcomings of polylactic acid, such as hydrophobicity and acidity of degradation products
.
Since hydrogels can provide an ideal water environment for proteins, the formation of material-body fluid interfaces is reduced, thereby reducing protein adsorption rate and slowing down the formation
of fibrous capsules.
Kissel et al.
of the University of Marburg introduced polyoxyethylene ether (POE) into a polylactic acid-glycolic acid copolymer (PLGA) to create a gel-like environment that improved the protein compatibility of the polymer, reduced the attachment of cells on the surface of the material, and improved biocompatibility
.

3.
Biological effects under different routes of administration

1.
Subcutaneous injection of the route of
administration of polylactic acid is generally injected subcutaneously
in the form of microsphere microcapsules or micelles.
Subcutaneous administration may cause inflammation and fibrous capsules
due to the build-up of the microcysts of the solvent and injection site microspheres.

Inflammation and fibrocyst formation have a lot to do with
the hydrophobicity of molecules.
Daugherty, the drug research and development department of an institution, and other studies compared the tissue response
of subcutaneous injection of microspheres.
The three microspheres he uses are polylactic acid, a dodecacarbon-modified polyacetic acid-glycolic acid copolymer (B-PLGA), and an unmodified polyacetic acid-glycolic acid copolymer (UB-PLGA).

Experiments show that the cell infiltration of the three microspheres is obviously different due to the difference in hydrophilicity, and the degree of cell infiltration is related to
the hydrophilicity and size of the material.

2.
Implant drug delivery system Implantation drug delivery system
is divided into surgical implantation subcutaneous and puncture introduction subcutaneously
.
There are two main forms of polylactic acid implantation and drug delivery system, one is to surgically implant the polylactic acid material wrapped in the drug; The other is to inject polylactic acid microspheres into the body
using a rapidly diffusing organic solvent as a solvent.

The compatibility of subcutaneous polylactic acid introduced by puncture is affected
by the toxicity of the solvent and the rate of drug release.
Dunn et al.
of the University of Oklahoma formed an implant of polylactic acid at the administration site, using NMP (N-methyl-2-pyrrolidone) or DMSO (dimethyl sulfoxide) as a solvent
.
Experiments have found that once injected into the body, the solvent quickly diffuses from the polymer gap, so that the polymer forms a biodegradable solid implant, due to the uncontrollable size and shape of the implant system, the release rate of the drug is also difficult to control, and may lead to a sudden increase in blood concentration due to sudden release: on the other hand, NMP and DMSO can cause dermal irritation, local necrosis, inflammation and edema
.

3.
Transocular route of administration
Due to the presence of the blood-eye barrier and self-clearance of the eye surface, it is difficult for the drug to stay
on the eye surface.
Polylactic acid can be used as a carrier, into which the drug is injected and surgically implanted, allowing for a sustained release of the drug
for a long period of time.
However, based on the special physiological structure in the eye, the inflammation caused by polylactic acid, and the effect of polylactic acid and its degradation products on vision remain to be seen
.

Hashizoe et al.
of the Department of Ophthalmology and Visual Sciences successfully used scleral suppositories made of PLA to continuously release acyclovir in the rabbit lens without serious inflammation and no malformations under microscopic observation
.
Therefore, the biocompatibility of this device is clinically acceptable
.
Simultaneous loading of fluconazole with PLGA suppositories also yielded desirable results
.
Both indicate that polylactic acid has good biocompatibility in the route of transocular administration
.

4.
The role
of immunity Polylactic acid good biocompatibility has been reflected
in many aspects.
Some researchers have used polylactic acid as a carrier of antigens and antibodies, which has played a corresponding immune role
in animals.
When polylactic acid is used as an antigen-antibody drug delivery system, it is found that drugs using polylactic acid can enhance the antibody antigen reaction and increase the efficacy
.
When used as antigen carriers, antibodies can increase the retrieval rate of antigens, so that the body can produce an immune response
more quickly.

Behera from India encapsulated Aeromonas hydrophila membrane protein (OMP) as an antigen in PLGA microspheres and entered the rainbow trout through parenteral administration, and found that PLGA can stimulate the body to produce humoral immunity and cellular immunity at the same time, enhance the extraction efficiency of dendritic cells and the phagocytosis
of macrophages.
Lavalle et al.
of the University of Plymouth in the United States will compare
PLGA as a carrier with antigen solution alone.
PLGA was found to prevent protein degradation in digestion fluids, enhance circulatory antigen retrieval, and enhance systemic and local antibody antigen responses
.

5.
Questions and prospectsPolylactic
acid is a polymer material approved by the US Food and Drug Administration (FDA) for medical use, and has maintained a long safety record
.
Whether it is used as a drug release system or a polymer medical device in vivo, many experiments have been done
on the biological effects and safety of polylactic acid.

Polylactic acid has good biocompatibility, but due to its strong hydrophobicity, it is easy to produce materials and tissue fluid or blood interface, resulting in inflammation and immune response, and the researchers have modified polylactic acid
.
PLA-PEG can overcome the hydrophobicity of polylactic acid and slow down the formation
of fibrous capsules to a certain extent.
Further research, such as the introduction of polyoxyethylene ether (POE) into PLGA, forms ABA triblock copolymer, can reduce the enveloping density
of inflammatory cells.
Modified products make polylactic acid have a broader application prospect.


In the biocompatibility study of the eye, polylactic acid as a drug carrier has no adverse effects on the eye, which provides the possibility
for clinical continuous treatment of the eye in the future.
In addition, polylactic acid has been found to increase efficacy as an antigen-antibody presentation system
.