Poly(lactic acid)... An interesting material for Tissue Engineering

In the last years, the progresses of our society and consequently, the technological and scientific developments, have driven significant advances in the discovery, improvement and production of polymers. 

Biodegradable polymers are derived from naturally occurring polymers that are found in all living organisms and can be classified into two groups: the agro-polymers (polysaccharides, proteins) and the biodegradable polyesters such as poly (lactic acid) (PLA), poly (hydroxyalkanoate) (PHA), aromatic and aliphatic copolyesters. Between these biopolyesters, PLA has caught the attention of polymer scientists as a potential biopolymer to substitute the conventional petroleum-based plastics. 

Poly (lactic acid) or PLA belongs to the family of aliphatic polyesters commonly made from α-hydroxyacids. This polymer has been the subject of many investigations for over a century. 

The most attractive advantages that distinguish PLA from the more common polymers are renewability, biocompatibility, processability and energy saving. First of all, PLA is a thermoplastic, high-strength and high-modulus polymer derived from renewable and degradable resources such as corn and rice, which can help alleviate the energy crisis as well as reduce the dependence on fossil fuels of our society. It is also  degraded by simple hydrolysis of the ester bonds, which does not require the presence of enzymes and in turn prevents inflammatory reactions. The hydrolytic products from such degradation process are then transformed into nontoxic subproducts that are eliminated through normal cellular activity and urine, making it an optimal material for biomedical applications. Moreover, this polymer has good thermal proprieties and thus it can be processed by film casting, extrusion, blow molding, injection molding and fiber spinning. This thermal processability is greater than other biomaterials such as poly (ethylene glycol) (PEG), poly (hydroxyalkanoates) (PHAs) and poly(ɛ-caprolactone) (PCL), contributing to the PLA application in textiles and food packaging fields. Finally, PLA production consumes 25-55% less fossil energy than petroleum-based polymers which will lead to significant reductions in air and water pollution and the total amount of water required for PLA production it is also competitive.    

        

However, confronted with many requirements for certain applications, Poly(lactic acid) has some disadvantages as its slow degradation rate through hydrolysis of the backbone ester groups, which can takes several years and can prevent its biomedical and food packaging applications. Another obstacle, unless it is properly modified, is the brittleness of this polymer, with less than 10% elongation at break; it is not suitable for demanding mechanical performance applications. PLA is also strongly hydrophobic and when it is applied as a tissue engineering material, because of its low affinity with cells, it can induce an inflammatory response from the tissues and living hosts. The last limitation is its limited gas barrier proprieties which prevent its complete access to industrial sectors such as packaging. From this point of view and considering its high cost, low availability and limited molecular weight, PLA has not received the attention it deserves, and that’s why the surface modification, the introduction of other components, or the surface energy, charge and roughness control have been examined.

Actually and in the biomedical field, micro and nanoparticles are a significant group of delivery systems, and the application of PLA is interesting due to its low toxicity and hydrolytic degradability. The most important properties of these systems are the drug release rate and the matrix degradation rate which are affected by the particle design and the material properties. Tissue engineering is also an area of interest for the PLA application, mainly in porous scaffolds to reconstruct matrices for damaged tissues and organs. 

• Tissue Engineering

The field of tissue engineering was created to improve and develop biological functions and it’s closely associated with methods to reconstruct living tissues by combining the cells and biomaterials. This association provides a scaffold, a temporarily supporting structure on which they can proliferate three-dimensionally and under physiological conditions.The advantages of tissue engineering over transplantation are that a donor is not required and there is no problem of transplant rejection. 

http://en.wikipedia.org/wiki/Tissue_engineering#mediaviewer/File:Tissue_engineering_english.jpg

A suitable scaffold for tissue engineering use should be biocompatible and have a good integration into host tissues without any immune response, be porous and have appropriate pore size and distribution for removing metabolic waste and allow cell and tissue growth. In addition, it must be biodegradable and mechanically able to support local stress and structure. Not all biomaterials have the capability of being used in this field, for example, although some metals have good mechanical proprieties and consequently being used in biomedical implants, they are not so advantageous for scaffolds because of their lack of degradability. Ceramics are also limited and despite good osteocondutivity and therefore mineralization, they have poor processability into porous structures.

Some linear aliphatic polyesters such as PLA and its copolymers, due to their structure and proprieties can be used as scaffolds. These polymers are approved by the FDA in biomedical field, but like the other materials, have some disadvantages like their slow rate of degradability, hydrophobicity and lack of functional groups, which conditions cells adhesion. A fibrous scaffold has significant advantages over polymer films in the high level of porosity needed to accommodate a large number of cells. This is where the pore diameter (interstitial space) becomes important for cell growth, vascularization, and diffusion of nutrients. 

Three-dimensional PLA porous scaffolds have been created for culturing different cell types, in cell-based gene therapy for cardiovascular diseases; muscle tissues, bone and cartilage regeneration and other treatments of cardiovascular, neurological, and orthopedic conditions. Osteogenic stem cells seeded on scaffolds of this material and implanted in bone defects or subcutaneously can recapitulate both developmental processes of bone formation: endochondral ossification and intramembranous ossification. Due to the high strength of PLLA mesh, it is possible to create 3D structures such as trays and cages. 

Several researches have shown that PLA-based hybrid materials are particularly promising and they have been successfully tested in many tissues such as bladder, bone, liver, cartilage and adipose. Chitosan/PLGA by heparin immobilization is an example of a novel scaffold that is being clinically tested. The introduction of chitosan into PLGA microspheres improves the attachment of biomolecules such as heparin because of chitosan’s reactive amino group. This heparinized chitosan/PLGA scaffolds with a low heparin loading showed a stimulatory effect on cell differentiation and may be used in bone regeneration.

For tissue engineering, the application of three-dimensional scaffolds as synthetic extracellular matrices allowed the cells proliferation and secretion while the scaffold gradually degrades. These 3D scaffolds, often consist of polymer/ceramic composites, such as a polymeric matrix filled with bioactive glasses, glass ceramics and calcium phosphates, that combine the advantages of the two types of materials. The polymers that are used in the matrix can be such as chitin and chitosan and collagen or synthetic polymers such as saturated aliphatic polyesters: polylactic acid (PLA), polyglycolic acid (PGA), polycaprolactone (PCL) and polyhydroxyalkanoates.

Three-dimensional electrospun fibrous scaffolds have been also studied for bone regeneration. Electrospinning uses an electrical charge to draw micro and nano scale fibers from a liquid and the use of these 3D materials like microfibrous PLLA scaffolds have reported a higher level of osteoblasts proliferation and a favorable substrate for cell infiltration and bone formation.

In cartilage tissue engineering, collagen and hyaluronan-based matrices are among the most used scaffolds, due to their substrates which are normally essential elements in native articular cartilage. The PLA is used as PGA/PLA copolymer under the trade name BioSeed-B and BioSeed-C by German industry (Biotissue Technologies AG, Freiburg, Germany). 

However, despite these recent developments, PLA-based materials still have an important limitation for tissue engineering - the risk of immune response and disease transmission. In the future, it’s expected the use of design scaffolds with in vivo experimentation, and coupling scaffold design with cell printing to create material hybrids to optimize tissue engineering treatments.