Biomaterials play an important role in disease treatment and health care. According to the nature of materials, biomaterials can be divided into inert materials and degradable materials. At present, the development of biomaterials shows inertness to degradability (hydrolysis and Enzymatic degradation) The trend of transformation suggests that many bio-inert devices that now have a temporary therapeutic effect (helping the body repair or regenerate damaged tissue) will be replaced by degradable material devices.
Compared with inert materials, degradable polymer materials are a more ideal medical device material. Inert devices generally have poor long-term compatibility and require secondary surgery, while degradable polymer materials do not have these defects. In the past 20 years, some new medical technologies have emerged in biomedicine, including tissue engineering, drug controlled release, regenerative medicine, gene therapy and bio-nanotechnology. These new medical technologies need to be supported by degradable polymer materials. Correspondingly, the development of degradable polymer materials has been promoted.
Degradable polymer materials need to have good compatibility throughout the degradation process, including the following:
Does not cause persistent inflammation or toxic effects after implantation in humans;
a suitable degradation cycle;
In the degradation process, having mechanical properties corresponding to the function of treatment or tissue regeneration;
The degradation products are non-toxic and can be excreted by metabolism or infiltration;
Processability. There are many factors affecting the biocompatibility of degradable polymer materials. Some properties of the material itself, such as the shape and structure of the implant, hydrophilic and lipophilicity, water absorption, surface energy, molecular weight and degradation mechanism, need to be considered.
This paper reviews the properties and degradation characteristics of several commonly used degradable polymer materials, including polyglycolide, polylactic acid, (glycolide-lactide) copolymer, polycaprolactone, polydioxanone, Polyhydroxyalkanoates, polytrimethylene carbonates and polyurethanes and polyether urethanes, etc., and their applications in medical devices, including implants, tissue engineering scaffolds, drug controlled release carriers, etc., are reviewed.
Polyglycolide (PGA)
PGA is the first synthetic degradable polymer material used in clinical medicine. It has a high degree of crystallinity (45% to 55%), and its high crystallinity gives it a large tensile modulus. PGA is insoluble in organic solvents, its glass transition temperature (Tg) is between 35 and 40 ° C, and its melting point (Tm) is higher than 200 ° C. It can be processed by extrusion, injection molding and molding. Due to its good fiber-forming properties, PGA was first developed as an absorbable suture.
In 1969, the first synthetic degradable suture line DEXON® approved by the US FDA was made of PGA. Because PGA has suitable degradability, excellent initial mechanical properties and biological activity, PGA nonwoven fabric has been widely studied as a tissue regeneration scaffold material. Currently, a scaffold material containing PGA non-woven fabric is being used in clinical trials.
In addition, PGA dural substitutes are also being studied because of their ability to help tissue regeneration and close the skin under a seamless line. The high crystallinity of PGA makes it have excellent mechanical properties. Among the degradable polymer materials used in clinical practice, self-reinforced PGA is the hardest, and its modulus is close to 12.5 GPa. PGA has also been developed as an internal fixation system (Biofix®) because of its good initial mechanical properties. PGA achieves degradation by random cleavage (hydrolysis) of the ester bond in the segment. Under the action of hydrolysis, the mechanical properties of PGA decreased within 1 to 2 months, and the mass loss occurred within 6 to 12 months. In vivo, PGA is degraded into glycine, which can be directly excreted in the urine or metabolized into carbon dioxide and water. High degradation rates, acidic and poorly soluble degradation products limit the use of PGA in biomedical applications, but these disadvantages can be overcome by copolymerization with other monomers.
Polylactic acid (PLA)
Lactide (LA) is a chiral molecule and there are two stereoisomers: L-LA (L-LA) and D-LA (D-LA), all of which are semi-crystalline. Racemic LA (DL-LA) is a mixture of L-LA and D-LA, the polymer of which is random. The crystallinity (0% to 37%) of poly L-LA (PLLA) is determined by molecular weight and processing parameters, and has a Tg of 60 to 65 ° C and a Tm of about 175 ° C. Because it is less hydrophilic than PGA, it has a lower degradation rate than PGA.
PLLA has high tensile strength, low elongation at break and high tensile modulus of elasticity (close to 4.8 GPa), making it an ideal medical load-bearing material, such as bone fixation devices. The PLLA bone fixation devices on the market today include BioScrew®, Bio-Anchor®, and MeniscalStinger®. In addition, PLLA can also be made into high-strength surgical sutures. In 1971, the PLLA surgical suture was approved by the US FDA, which has better performance than DEXON®. PLLA can also be used in other medical fields, such as ligament repair and reconstruction, drug-eluting stents, and targeted drug delivery. In 2007, the US FDA approved an injectable PLLA product (Sculptra®) for the treatment of facial fat loss or atrophy caused by human immunodeficiency virus (HIV). The degradation rate of PLLA is slow, and it takes 2 to 5.6 years for the high molecular weight PLLA to completely degrade in the body. Factors such as crystallinity and porosity can affect its degradation rate.
Under hydrolysis, PLLA showed a decrease in mechanical properties within 6 months, but it took a long time for quality loss to occur. Therefore, in order to obtain better degradation performance, the researchers copolymerized L-LA with GA or DL-LA. Resomer® LR708 is a random copolymer obtained by copolymerization of L-LA and DL-LA (mass ratio 70:30). PDLLA forms a random copolymer due to the random distribution of L-LA and D-LA. The Tg is between 55 and 60 °C, and the strength is greatly reduced, which is caused by the random arrangement of molecular chains. Under the action of hydrolysis, PDLLA showed a decrease in mechanical properties within 1 to 2 months, and mass loss occurred within 12 to 16 months. Compared with PLLA, PDLLA has the characteristics of low strength and high degradation rate, and is an ideal material for drug transport carriers and tissue regeneration scaffolds (low strength). PLA achieves degradation by random cleavage (hydrolysis) of ester bonds in the segment. The primary degradation product is lactic acid, which is a by-product of normal metabolism of the human body. Through the citric acid cycle, lactic acid can be further degraded into carbon dioxide and water.
Copolymer (PLGA)
It is found that PLGA is a random copolymer when the mass ratio of LA to GA is between 25/75 and 75/25. Studies by RAMiller et al. show that PLGA with a mass ratio of LA to GA has the fastest degradation rate of 50/50. .
PLGA with different monomer mass ratios has been widely used in clinical practice. The PLGA under the trade name Purasorb® PLG is a semi-crystalline copolymer with a mass ratio of LA to GA of 80/20; the mass ratio of L–LA to GA in the multi-strand Vicryl® is 10/90. The upgraded version of VicrylRapid® is also available, and the upgraded version after irradiation has a faster degradation rate;
PANACRYL® is another commercial PLGA suture. In addition, PLGA is also used in other medical applications, such as mesh (VicrylMesh®), skin grafting materials and dural substitutes. Tissue engineering skin grafting uses VicrylMesh® as a scaffolding material. The ester bond in PLGA is broken by hydrolysis, and its degradation rate is affected by many factors, such as: LA to GA mass ratio, molecular weight, material shape and structure. PLGA has the characteristics of easy processing and controllable degradation rate. It is approved by the US FDA and can be applied to human body. It has been widely studied in the fields of controllable drug/protein transport systems and tissue engineering scaffolds. PLGA has the function of promoting cell adsorption and proliferation, which makes it have potential tissue engineering applications. Many studies have prepared micro-nano-scale PLGA three-dimensional scaffolds. Figure 1 shows the three PLGA structures obtained by different methods.
Another important application of PLGA is drug carrier and targeted release. PLGA can exist in many forms such as microspheres, microcapsules, nanospheres and nanofibers. Drug release parameters can be controlled by adjusting the performance of PLGA. Since PLGA is an overall erosion degradation, that is, both surface and interior degradation, it is difficult to achieve zero-order release.
Polycaprolactone (PCL)
PCL is a semi-crystalline linear polyester obtained by ring-opening polymerization directly from the relatively inexpensive monomer ε-caprolactone (ε-CL). PCL has good processability, is easily soluble in many organic solvents, and has a low Tm (55-60 ° C) and Tg (-60 ° C). PCL has a very low tensile strength (23 MPa) and a high elongation at break (700%). In addition, it can also be copolymerized with a variety of polymers. The degradation cycle of PCL is 2~3a, which is often used as a long-term drug controlled release carrier. The micron-nano-grade PCL drug delivery carrier is in the research stage.
PCL is also used in tissue engineering scaffold materials. H.Tseng et al. used three different methods to increase the hydrophilicity of PCL, and then blended with polyethylene glycol (PEG) to form an anisotropic hydrogel fiber scaffold. The scaffold has a good biocompatibility and controllable structure and is a potential heart valve tissue engineering scaffold material. ZhaoJing et al. prepared micellar nanoparticles of PCL-PEG copolymer, which can be used as a transport carrier for picropodophyllin (anticancer drug) in vitro (37 ° C) and phosphate buffer (PBS, PH = In 7.4), 70% of the drug can be released in 96h, which is in good agreement with the Higuchi equation, so PCL-PEG copolymer nanoparticles containing PPP are expected to be injectable preparations. Because of the slow rate of PCL degradation, researchers have developed several types of copolymers containing PCL in order to achieve faster degradation rates. The copolymerization of ε-CL and DL-LA can achieve a faster degradation rate. Similarly, ε-CL can also be copolymerized with GA to make surgical sutures. Its hardness is smaller than that of PGA, and monofilament suture MONACRYL® is like this. A product.
In addition, multi-block copolymers composed of ε-CL, LA, GA and PEG can be applied to drug controlled release systems. It is mainly used as a carrier for small and medium-sized bioactive molecules (SynBiosys®). BJ Hong et al. The method of small interfering RNA (siRNA) vector is simple and convenient, and it has obvious inhibitory effect on tumor cell proliferation.
Polydioxanone (PDS)
Although PLA and PGA can be made into general-purpose degradable multifilament sutures, multi-filament sutures have a high risk of infection in use, and multi-filament sutures also have large frictional force when penetrating tissue, so many studies Looking for polymer materials suitable for making monofilament sutures. PDS is a degradable polymer material suitable for making monofilament sutures. In the 1980s, the first PDS monofilament suture PDS® was launched. In addition, PDS fixing screws (Orthosorb AbsorbablePins®) are also used in orthopedics, which are mainly used for the fixation and repair of small bones and cartilage. PDS is a colorless semi-crystalline polymer which can be obtained by ring-opening polymerization of p-dioxanone with a Tg of -10 to 0 °C.
As a member of the polyester, its degradation is also achieved by random cleavage of the ester bonds in the chain. High crystallinity and hydrophilicity give PDS a moderate rate of degradation. In vivo, PDS is degraded to glyoxylic acid, which can be excreted in the urine, and can be further degraded to glycine, which is consistent with the degradation products of GA. The tensile modulus of elasticity (close to 1.5 GPa) of PDS is very low compared to PGA. Under the action of hydrolysis, the mechanical properties of PDS decreased within 1 to 2, and the mass loss occurred within 6 to 12 months.
Polyhydroxyalkanoate (PHA)
PHA-based degradable polymer materials include poly-3-hydroxybutyrate (PHB), poly 4-hydroxybutyrate (P4HB), copolymer of PHB and poly-3-hydroxyvalerate (PHBV), etc., of which PHB The application is the most extensive. In 1920, researchers first discovered that Bacillus megaterium produced PHB. Since then, studies have found that several other strains can also produce PHB. PHB is a semi-crystalline isotactic (stere) polymer with a melting point between 160 and 180 °C. The degradation of PHB belongs to surface erosion degradation, which is different from the common overall erosion degradation. In addition to the method of bacterial preparation, the researchers have also developed a chemical synthesis process. B. Panchal et al. prepared a PHB from a monomeric β-butyrolactone by ring-opening polymerization, which is equivalent to the PHB prepared by bacteria.
Copolymer P(HB–HV) of 3-hydroxybutyrate (HB) and 3-hydroxyvaleric acid (HA) has a semi-crystalline structure similar to PHB, and its Tg is –5 to 20 ° C, depending on the HV content. Differently, the magnitude of Tm drop of P(HB–HV) is also different. PHB and P (HB-HV) are easily soluble in organic solvents and are easily processed into articles of various shapes and structures. Due to the reduced friability of P(HB-HV), it is more suitable for use in biological materials. In addition, P (HB-HV) has piezoelectric properties, which makes it applicable to orthopedics, which can promote bone healing due to electrical stimulation.
PHB can achieve zero-order release when used as a drug carrier, but its degradation cycle is longer. In order to improve its degradation properties, researchers often copolymerize it with hydrophilic substances, generally PEG. AVMurueva et al prepared PHA series microspheres as drug transport carriers. The drug loading of microspheres affected the size and zeta potential of the microspheres. The zeta potential decreased after drug loading, and the average diameter of the microspheres became larger. The prepared PHA series microspheres were prepared. Has excellent biocompatibility. PHA-based degradable polymer materials have potential applications against infection, and studies have shown that PHA drug delivery systems can provide and maintain appropriate antibiotic solubility at the site of infection. PHA has been widely used in medical devices, cardiovascular tissue engineering, nerve conduit tissue engineering, bone tissue engineering, cartilage tissue engineering, drug delivery vehicles, and healthcare.
Polytrimethylene carbonate (PTMC)
PTMC is an aliphatic polyester elastomer that is not mechanically strong and is commonly used as a soft tissue regeneration scaffold or drug delivery vehicle. The degradation rate of PTMC in vitro and in vivo is very different. It does not degrade in 2a in phosphate buffer (pH=7.4), but it is implanted into the subcutaneous of the back of the mouse, and it will degrade quickly, mainly as PTMC. The shape changed, but its molecular weight did not change, indicating that PTMC had surface erosion degradation in the body. Different molecular weight PTMCs have different degradation rates. The degradation rate of high molecular weight PTMC is much faster than that of low molecular weight PTMC. This may be because low molecular weight PTMC is more hydrophilic, and the hydrophilic surface reduces lipolytic enzyme activity. The degradation rate is slowed down. ZengNi et al. prepared a PTMC barrier film for guiding bone regeneration in oral and maxillofacial surgery. Compared with collagen film, PTMC membrane can induce more bone tissue.
In order to improve the penetration of drugs into the blood-brain barrier and improve the concentration of drugs in glioma cells, JiangXinyi et al. prepared 2-deoxy-D-glucose modified PEG-PTMC copolymer nanoparticles with uniform distribution. The ideal size (71 nm), higher encapsulation efficiency, and appropriate paclitaxel loading, in vitro and in vivo tests indicate that the microparticles have excellent blood-brain barrier penetration and targeting of intracranial tumor cells.
The mechanical properties of PTMC are poor. The researchers mostly copolymerize it with other linear lactones to improve its mechanical properties. However, PTMC and its copolymers have good degradability and biocompatibility. RAWach et al. prepared PLLA–trimethylene carbonate (TMC) copolymer and methylcellulose (MC) hybrid porous catheter scaffold, in which MC acts as a carrier for biologically active substances such as growth factors. Physicochemical properties and toxicity test results show that the catheter is very suitable for nerve conduit regeneration, which can be used for regeneration of the peripheral nervous system after injury.
Copolymers of GA and TMC have been developed as flexible sutures (Maxon®) and orthopedic fixation devices (Acufex®). In addition, copolymerization of GA, TMC and dioxane can produce low-rigidity copolymers with degradation cycles. 3 to 4 months, can be used to make sutures (BioSyn®).
Polyurethane (PUR) and polyether urethane (PEU)
Non-degradable PUR and PEU have good biocompatibility and mechanical properties and can be used to make long-term medical implants such as pacemakers and artificial blood vessels. Because of the synthetic pathways of non-degradable PUR with good biological properties and diversity, researchers began to try to develop degradable PUR. PUR is generally prepared by polycondensation of a diisocyanate with a diol/diamine, but common diisocyanates such as 4,4'-diphenylmethane diisocyanate (MDI), toluene-2,4-diisocyanate (TDI), etc. Too much toxicity, the researchers developed other aliphatic diisocyanates [such as 1,4-butane diisocyanate (BDI), hexamethylene diisocyanate (HDI), succinyl chloride (LDI), isophorone diisocyanate ( IPDI) and lysine triisocyanate, etc.] to synthesize degradable PUR.
LDI reacts with DL–LA, CL and other monomers to produce degraded PEU, and its properties can be adjusted over a wide range. In these PEUs, the aliphatic polyester constitutes a soft segment and the polypeptide constitutes a hard segment. J.Podporska-Carroll et al. used a phase reversal technique to prepare a poly(ester-urethane) urea (PEUU) three-dimensional porous scaffold. The human osteosarcoma MG–63 cells were inoculated into the scaffold for 4 weeks, and the results showed that the scaffold had supporting cell adsorption. The role of growth and proliferation is a potential alternative to cancellous bone. JRMartin et al. prepared a selectively degraded polythioketal urethane (PTK-UR) tissue engineering scaffold that is selectively degraded by reactive oxygen species (ROS) produced by cells to achieve coordination between tissue growth and material degradation. ROS is a key mediator of cell function, especially in areas of inflammation and tissue healing. The body's natural response to implants is inflammation and ROS. In addition, the researchers also prepared PH-sensitive PUR, which can self-assemble to form micelles, and is expected to become a multi-functional active intracellular drug transport carrier.
In tissue engineering, researchers are developing PEU (Degrapol®) as a scaffold material; in orthopedics, researchers have developed an injectable two-component PUR (PolyNova®) that is in the form of a liquid under arthroscopy. Used to provide suitable attachment and support after polymerization at body temperature in situ, exhibiting equivalent or superior performance to commonly used bone cement, and it also promotes cell adhesion and proliferation.
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