BIODEGRADABLE IMPLANTS IN ORTHOPEDICS AND TRAUMATOLOGY. OUR FIRST EXPERIENCE
Regional Clinical Center of Miners’ Health Protection, Leninsk-Kuznetsky, Russia
National Research Center “Kurchatov Institute”, Moscow, Russia
During the last 30 years the development of traumatology and orthopedics has significantly improved the outcomes of treatment of the locomotor system injuries, mainly owing to development of the used techniques of osteosynthesis and surgical fixation. During that period the fundamental studies of biomechanics of fractures, strength properties of the implants and development of surgical techniques were conducted. The materials, which are implanted for supporting the mechanical properties of the broken bones during the healing period, should be characterized with sufficient strength, wear resistance and durability. Also they should be safe and easy to use. The modern gold standard is use of titanium fixators, which are strong and also inert in relation to the patient’s tissues.
However, like all other implants, the titanium fixators are not without disadvantages. The main disadvantages include:
- a possibility of development of endogenous infection;
- a possibility of adaptive rebuilding of a bone (stress shielding) that can result in bone resorption and decrease in its strength;
- pain; local irritation.
The factors lead to further removal of the fixators. It inevitably causes a new surgical injury with all specific risks. As result, the traumatologists showed their interest in the materials resorbing in the body. So, the biodegradable materials appeared.
The literature describes the variety of the similar interchangeable terms characterizing the ability to degradation: biodegradable, bioabsorbable, bioreabsorbed, bioerodible. The meaning of the prefix “bio” and the terms are interpreted in different ways [1]. For example, biodegradation may be interpreted as degradation of material caused by enzymes, bacteria, microorganisms etc. However in this review the term “biodestruction” (biodegradation) is interpreted as degradation of material in physiological (bio) conditions regardless of its mechanism. It can be hydrolytic, enzymatic, oxidative etc. Degradation can happen along the whole volume of material or only on the surface; it is determined by the relationship between the rate of degradation and the rate of water diffusion to the volume of material [2]. The ideal biodegradable material for production of fixators should be strong, and the rate of degradation (decrease in strength) should be near the rate of restoration of strength of bone tissue. However biodegradable materials should correspond to many other factors:
- non-toxicity or absence of a negative response to surrounding tissues;
- appropriate mechanical characteristics (strength, plasticity);
- radiopacity;
- a possibility for sterilization without loss of necessary features etc.
Currently, such materials are alloys of various metals with magnesium, calcium phosphates, and various natural and synthetic polymers. The synthetic and natural polymers are most popular in medicine owing to availability and versatility [3]. The synthetic polymers have such advantages as controlled molecular structure and time of biodegradation, absence of allergic responses during implantation. The highest popularity is associated with polyesters, i.e. poly (α-hydroacids) and, firstly, copolymers based on lactide and glycolide [4]. Most current implants for fixation are produced from these polymers [5]. Clinical use of the biodegradable polymers on the basis of lactide and glycolide started with polyglycolide surgical sutures [6]. Afterwards the wide range of the materials and the medical systems has been developed: nonwoven materials, sponges, scaffolds, coats, fixators, the systems for controlled delivery of drugs and many others [7, 8]. Owing to the aggravated ecological situation, the perspective region for use of polylactide is production of biodegradable packing, disposable cutlery and others [9].
Polyglycolide (PGA) is a solid crystallic polymer with the melting temperature of 224-230°C. Polylactic acid (polylactide, PLA) is a polymer with the melting temperature about 160-180°C and the glass transition temperature of 50-60°C. Poly (L-lactic acid) PLLA is more widely used for orthopedic implants, because this material preserves its primary strength longer as compared to poly (D,L-lactic acid) PDLA, which combines both enantiomers [10]. PGA relates to the category of quickly degraded polymers. Endosseous PGA screws showed the full degradation within 6 months [11]. Contrariwise, PLLA demonstrates longer period of degradation, and the residuals can be identified in tissues within 5 years after implantation [12]. PLLA is produced with lactide polymerization – the cyclic ester of lactic acid. For synthesis of PLLA with the controlled characteristics and time of degradation it is necessary to use the optically pure L-lactide and to conduct the polymerization in optimal conditions [13].
Which main characteristics of the polymers are to be considered for estimation of the quality? Firstly, they are kinetics of degradation, the physical and mechanical characteristics and biocompatibility.
Degradation is determined by chemical response of polymer chain that results in some changes in its molecular structure and, mainly, in molecular mass that accompanied by changes in the mechanical patterns of the item and its shape. Degradation of poly (α-hydroxyacids) can be realized with hydrolytic or enzymatic pattern. At the first stage, the polymer chain is exposed to hydrolysis that leads to decrease in molecular mass of the material. At the second stage, the oligomeric chains and low molecular products of degradation are converted with the enzymes and the microorganisms [14]. Kinetics of degradation is directed by means of regulation of the composition and supermolecular structure of the material. The main characteristics influencing on the process of degradation are:
- Chemical structure of the polymer
The chemical structure of the polymer makes significant influence on sensitivity to hydrolysis. The polyglycolide does not contain any hydrophobic methyl groups. Therefore, hydrolysis of its chain goes faster as compared to the polylactide. By means of changing in the relationship between the links of lactide and the glycolide in the copolymer, one can regulate the time of biodegradation within the high range (from several months to several years).
- Molecular mass of the polymer
The polymer products with higher molecular mass demonstrate longer preservation of the physical and mechanical features. Wu et al. showed that the absolute decrease in molecular mass happened faster in high molecular polymers as compared to polymers with lower mass [15]. Hydrolysis of lactide- and glycolide-based copolymers is a response of the first order, at least at the first stages of the process.
- Degree of crystallinity
Crystallinity is a measure for adjustment of interaction energy and density of the material. Water approach to more dense crystal regions of the material is difficult, with lower degradation than in less dense amorphous regions. Firstly, amorphous regions degrade, and the degree of crystallinity of the material increases along with its degradation; it decreases only after appearance of degradation of crystal regions [16].
Kinetics of biodegradation depends on many other factors such as the form and thickness of an implant, temperature of pH-medium, the individual level of enzymes in the body and others [15]. One can suppose that thicker massive items demonstrate faster degradation than the thin ones, but not in all cases. Some studies showed that degradation of polylactide cylinders resulted in their accumulation in the deep layers of the item because of the low rate of diffusion of acid products of degradation. It causes the autocatalytic acceleration of the process [2, 17]. As result, hollow cylinders appear, i.e. degradation of the item is more rapid inside the item than on its surface. The rate of biodegradation of one and the same item can vary for different patients. The enzymes (their level is individual) take the role of “biological catalyzers” promoting the hydrolysis [18].
Mechanical properties
The physical and mathematical properties of the products on the basis of poly (α-hydroxyacids) are determined by the molecular and supramolecular structure of the material. Also they depend on the construct and the technique of production of an implant. Polyglycolide demonstrates the highest degree of crystallinity and elasticity coefficient (the table). However this material is not used for production of biodegradable fixators because of the high rate of degradation and difficult recycling relating to the similar values of temperature of melting and destruction. The polylactide and its copolymers are characterized with lower elasticity ratio (ac compared to the bone), but with similar strength.
| Table | |||||
| The physical and mechanical features and terms of biodegradation of various materials for traumatology and orthopedics, comparison with a bone [19] | |||||
| Material | Modulus of elasticity, HPa | Strength, Mpa | Deformation during rupture,% | Duration Strength retention, months | Time of complete degradation, months |
| Bone | 7-40 | 90-120 | |||
| Metal and ceramics | |||||
| Titanium alloy | 110-127 | 900 | 10-15 | - | - |
| Stainless steel | 180-205 | 500-1000 | 10-40 | - | - |
| Magnesium | 41-45 | 65-100 | - | < 1 | 0.25 |
| Hydroxyapatite | 80-110 | 500-1000 | - | > 12 | > 24 |
| Tricalcium phosphate | - | 154 | - | 1-6 | < 24 |
| Áèîðàçëàãàåìûå ïîëèìåðû / Biodegradable polymers | |||||
| Polyglycolide | 7 | 340-920 | 15-20 | 1 | 6-12 |
| Poly (L,L-lactide) | 2.7 | 80-500 | 4-10 | 3 | > 24 |
| Poly (D,L-lactide-co-glycolide | 2 | 40-550 | 3-10 | 1 | 1-12 |
| Polycaprolactone | 0.4 | 20-40 | 300-500 | > 6 | > 24 |
| Polyutheranes based on polycaprolactone and polyethylene oxide | 0.001-0.01 | 1-50 | > 500 | 1 – 6 | 6-24 |
Different ways can be used for increasing the physical and mathematical characteristics of the implants: orientation [20], production of reinforced [21, 22] or compound material [23, 24].
Sterilization is an important factor influencing on the mechanical properties of the products or materials. The polymers are more susceptible to action of the sterilizing agents as compared to metals. As s rule, sterilization leads to decrease in molecular mass and the physical and mathematical properties of the copolymer materials [25]. Sterilization of the polymers with use of warm heat and autoclaving cannot be performed because the influence of high temperature on the polymer material causes softening, changes in geometry and thermal destruction. Sterilization with ethylene oxide, hydrogen peroxide, beta- and gamma-exposure is the most efficient and sparing technique of polymer sterilization [26].
Biodegradable constructs for traumatology and orthopedics
Traumatology and orthopedics are the common fields where biodegradable implants are used [27]. The first reports about the clinical administration of PLA and PGA implants relate to 60s of the previous century [28, 29]. Since that time the development of biodegradable implants was oriented to achievement of optimal rate of degradation, rigidity and plasticity. Also the implementations included the complex systems including screws and plates for surgery in specific skeletal regions.
Advantages of biodegradable systems
The main advantage of biodegradable fixators (as compared to metal) is full absorption that prevents recurrent surgery causing additional injury; it is especially common for peri- and intraarticular injuries.
The next important moment of bioabsorbable implants is X-ray-negative characteristics. In many cases only MRI estimates the degree of bone regeneration, but metal fixators create the impossibility for such examination. Therefore, radioparent fixators create the solution for such situations.
The event of adaptive rebuilding of the bone in response to contacting with metal fixators, known as stress shielding, often causes periimplant osteoporosis decreasing the quality of the bone. It especially often happens in the cases, when an implant is needed only for specific stages of reparative osteogenesis, but afterwards it plays the negative role. In such cases the use of absorbable materials for osteosynthesis may be efficient. Unlike the metals, the physical and mathematical characteristics of polymer implants are similar or demonstrate weaker patterns. Therefore, the use of polymer biodegradable implants should not be accompanied by adaptive rebuilding of the bone and osteoporosis.
The modern fields of use
At the modern stage of traumatology and orthopedics the injuries have been determined, where biodegradable systems are efficient and competitive as compared to the classical fixators [27]. The biodegradable implants are appropriate for fracture stabilization, osteotomy, bone grafting and bone union, especially for spongious bones, as well as for connections of ligaments, tendons, meniscus ruptures and for other structures of soft tissues. After the analysis of the modern literature about the biodegradable systems, one can arrange the injuries according to the rate of use:
Knee joint
Knee joint surgery can be divided into two parts – opened and arthroscopic. Knee joint arthroscopy is the field, where the absorbable implants are used very often [11, 13]. The first taken is probably given to the use of interferential screws for fixation of the anterior cruciate ligament. The modern techniques of plastic surgery with use of own tendons or allomaterials give better materials namely with interferential screws, which create the bone fixation in the channels without development of inflammatory responses within 12-36 months [31, 32].
Transchondral fractures are enough efficiently treated with the bone pins during arthroscopic operations and arthrotomy. Suturing for extensive meniscus ruptures is appropriately to be performed with vycril and its analogues. One should note that vycril sutures (copolymer of glycolide and lactide 90:10) were the first absorbable materials which were widely used from 1962 [33].
Shoulder joint
Development of arthroscopic techniques for the shoulder joint has made the significant influence on the opinions by the traumatologists concerning the characteristics of injuries to the rotation cuff and the acetabular rim according to Bancart. Such injuries are successfully treated with “anchors”, which allow fixing the soft tissue formations to the bone. The use of biodegradable fixators gives complete preservation of sliding properties of tendons and the articular rim [34, 35].
Foot surgery
The use of polymer fixators for foot surgery is determined by the anatomic construction of the foot. From one side, the foot consists of the small bones with lower time of union in comparison with the long bones (6-8 weeks), but, from other side, the foot contains a lot of joints which are susceptible to contractures during long term blocking. Polyglycolide and polylactide are the most popular biodegradable polymers with preservation of the strength characteristics during 6-8 weeks, which are necessary for bone union and subsequent absorption. These properties allow the use for different types of foot osteotomy which are common in treatment of platypodia and other deformations of the foot [36-38].
At the present time, the toolkit by traumatologists include the biodegradable implants which are used for fractures of shoulder condyles, the distal radial and ulnar bones, the greater tubercle and other metaphysic regions. Usually these fixators are screws or pins. There are biodegradable nets for reconstruction of the acetabulum, but their use is limited.
Pediatric traumatology
Wide implementation of polymers was firstly initiated in pediatric traumatology. Bostman et al. showed that self-reinforced absorbable nails were successfully used for fixation of fractures in the region of growth of the bone in children [39]. In 1991 the comparison of the self-reinforced absorbable nails with metal fixators was made in the study of children with humerus fracture [40]. The biodegradable screws were quite solid for fixation of subtalar arthrodesis in children [41]. Less strict requirements to strength of pediatric fixators allow the extension of indications for fixation of other segments.
Disadvantages
The main disadvantage limiting the use of the biodegradable systems is their low strength as compared to the metal fixators. It does not permit to use massive plates and nails which are necessary for stable functional osteosynthesis of the long bones.
The next relative disadvantage is high price of the biodegradable systems. The necessary properties of these fixators significantly increase the price. The possible solution of this problem is development of new production technologies and increasing rates of production that can decrease the wholesale price.
Perspectives
Concerning the perspectives of use of polymers in traumatology and orthopedics it is necessary to separate two directions:
- development of new materials with regulated properties;
- addition of new properties to existing materials.
The perspectives of the first case are development of composition materials with various non-organic fillers [19, 23, 24]. The second case relates to the studies of inclusion of pharmaceuticals (for example, antibiotics) into the materials that leads to long term release into tissues and prevention of postimplantation inflammation [42].
The requirements to the ideal implant include the appropriate strength, with mean time of degradation of 6-7 months (after completion of most processes of bone regeneration), the availability of the osteoinductive properties for stimulation of reparative regeneration, low price for use in clinical traumatology and orthopedics.
Investigation of physical and chemical characteristics of biodegradable pins
The biodegradable constructs Bioretec (Finland) were used during the operations in Regional Clinical Center of Miners’ Health Protection. The important characteristics of the polymer are the chemical composition and time of biodegradation, i.e. the main determinants of kinetics of biodegradation. The methods of nuclear resonance and gel-permeation chromatography were used for investigation of these characteristics. The figure 1 demonstrates NMR-range of the biodegradable pin. The multiplet in the region of 5.0-5.3 parts by weight corresponds to the protons of CH-groups of L-lactide, but the multiplet in the region of 4.5-5.0 is the response of CH2-groups of glycolide [43]. With use of the integral intensity of these signals one can calculate the chemical composition of the sample – 86 mol % of L-lactide and 14 mol % of glycolide. One should note the absence of other signals indicating the presence of admixtures in the sample. The signal with the chemical shift 7.24 parts by weight corresponds to chloroform, which was used for dissolving the sample before the analysis.
Figure 1
Nuclear magnetic resonance spectrum of a biodegradable pin on the basis of the copolymer lactide with glycolide. The level of links L-lactide/ glycolide = 86/14
The figure 2 demonstrates the molecular mass distribution of the pin estimated with chromatography. The weight-average molecular weight Mw (calculation with relation to polystyrene standards) was quite high (364,000 Da). The polydispersity index (PDI) characterizing the range of molecular mass distribution was 2.0.
Figure 2
Molecular and mass distribution of the sample of a biodegradable pin. Weight-average molecular weight Mw = 364,000 Da
It was important to determine the presence of possible changes at temperature of 37°C. This estimation was performed with differential scanning calorimetry with dynamic mode. The figure 3 demonstrates the thermographs of the first and second heating.
Figure 3
The thermographs of the first and second heating the sample of a biodegradable pin
The thermographs show that the glass transition temperature (when the material becomes soft) significantly exceeds the body temperature and consists 60°C. Also one may conclude that the sample has the amorphous structure, but it can partially crystallize during 100-140°C.
Therefore, the examinations of the material of the biodegradable pin showed the chemical correspondence to the producer’s data and absence of admixtures. High molecular mass of the sample provides slow degradation of the product.
Practical experience with biodegradable constructs
24 operations were conducted with use of the biodegradable constructs in 2015. Mainly, the fragments were fixed in the region of small joints (feet and hands). The results were achieved:
- inflammatory events were not identified;
- union was achieved within the usual time frames in 19 patients; union was in progress in 4 patients;
- one patient demonstrated the secondary displacement; the fixator was used for dislocation of the big segment (dislocation of the acromial end of the clavicle) and it required for recurrent surgery with the standard fixators;
- all patients received the additional external immobilization for additional fixation, because the operating surgeons were not sure enough in relation to the strength of fixation;
- X-ray signs of presence of the fixator were available during 5 months (for the patients with completed treatment);
- time of surgery was 15 minutes longer on average that was determined by proper adherence to the recommendations for using the described systems.
Therefore, it is early to speak about the conclusions, but we can say some first impressions about the biodegradable fixators.
The used fixing systems have the significantly lower rigidity as compared to metal analogues. As result, it requires the obligatory use of external fixators, resulting in increase in time of postsurgical recovery. From other side, the fixators disappear in 5-6 months. It prevents discomfort in the approach region and recurrent surgery for removal of fixators.
The biodegradable fixators have the advantages. However it is necessary to solve the problem of weaker mechanical characteristics as compared to the metal analogues. The perspective direction is development of biodegradable constructs of the new generation with improved mechanical properties and bioactive features.
The study was conducted with support from the Ministry of Education and Science of the Russian Federation (the unique identifier of the project RFMEFI60414X0081).