**2. Polymer Enhancements**

## *2.1. Copolymers and Polymer Blends*

Copolymers are favourable as they combine the beneficial properties of the monomeric species whilst simultaneously negating their disadvantageous properties. The same applies for polymer blends and the polymers that constitute these blends. This results in the possibility of a range of materials with desirable properties, including tailored material degradation rate, tunable biophysical, and biochemical properties [10]. Over the years, there has been a wide range of copolymers investigated for bone fixation applications, with copolymerisation being the key feature. Some of the most common polymers investigated include poly-L-lactide (PLLA), poly( D-lactic acid) (PDLA), poly( D,L-lactic acid) (PDLLA), and polyglycolic acid (PGA). These are summarised in Table 1.




**Table 1.** *Cont.*

Polylactic acid (PLA) is an aliphatic, biodegradable polyester used in a range of biomedical applications [21–23]. PLA polymers are used in bone fixation applications as it is possible to tailor the rate and degree of crystallinity, and, thereby, mechanical properties, degradation behaviour, and processing temperatures [5]. These are achieved through controlling the stereochemical architecture and the molecular weight of the polymer. Two stereoisomers of PLA are PLLA (poly(L-lactide) and PDLA poly(D-lactide) (Figure 1). PDLA is amorphous because of the racemic mixture of monomer, which disturbs crystallinity; consequently, erosion occurs at a significantly faster rate compared with PLLA [24–27]. To compare the two, a highly crystalline PLLA will take 2–5 years [28] to degrade in a normal physiological environment in vivo and in vitro (pH 7.4, phosphate-buffered solution (PBS), and incubated at 37 ◦C) [29]. An amorphous poly(D,L-lactic acid) (PDLLA) shows loss of integrity in 2 months and complete degradation in 12 months under similar conditions [30,31].

**Figure 1.** Enantiomer structures of PLA monomer [32].

PLLA and PDLA have been used extensively as copolymers to create materials for bone fixation applications [20,22,23,33,34]. They can also be combined to form poly(D,Llactic acid) PDLLA, with ratios of each polymer being varied. By controlling L/D ratios, a variety of different mechanical properties and degradation profiles can be obtained and implemented for bone fixation at various sites [35]. Poly-L/DL-lactide (70/30) plates have been successfully used in maxillofacial applications where an enhanced degradation rate is necessary to eliminate oedema formation; which can occur as a result of the slow degrading PLLA [11]. The strength of these plates is comparable to those of PLLA. Poly-D (2%),L (98%)-lactide interference fixation screws have been used in clinical applications, displaying no adverse side effects and a good rate of degradation due to the D isomer in

the copolymer [12]. Superior thermal and mechanical properties, compared to 100% pure L- or D- lactide polymers, have been reported from the production of stereo-complexes of enantiomeric PLAs. A polymer stereocomplex can be defined as "a stereoselective interaction between two complementing stereoregular polymers, that interlock and form a new composite" [36]. This results in a material with enhanced physical properties due in part to the formation of crystallites with intermolecular crosslinks [5,26,37–39].

Self-reinforcement (SR) is a form of copolymerisation where a composite structure is formed from a polymer matrix being reinforced with oriented reinforcing units, such as fibres, fibrils, or extended chain crystals. These units are composed of the same material as the matrix [40]. This technique can produce a range of polymeric devices of very high strength, including poly-L/DL-Lactide (SR-P(L/DL)LA) 70/30, which was developed for use as miniplates and miniscrews for anterior mandibular fracture fixation [40]. The matrix material, PLDLLA, was formed into a composite structure by reinforcing with the same material (PLDLLA) and was reported to have bending strengths of up to 400 MPa [40]. Self-reinforced materials were developed and enhanced through controlling copolymer ratios (L/D). Through blending the L/D isomers, it is possible to obtain fracture fixation plates that are bendable at room temperature without the application of heat, which can be required for other types of non-ductile resorbable materials used in fracture fixation [22,41–43]. SR-PDLLA/PLLA (40 PDLLA:60 PLLA) showed faster absorption in vivo compared with SR-PLLA, possesses sufficient mechanical properties for fixation of osteotomies, and displays no adverse foreign body reactions at 48 weeks post implantation [44]. Highly oriented polyester fibres were used as reinforcement in self-reinforced polymers or single polymer composites [45]. PLLA matrices with PLLA fibre reinforcement produced materials with increased strength values compared to unreinforced PLLA [46,47] (bending strength of 200 MPa and shear strength of 94–98 MPa), appropriate for treatment of the cortical bone in certain fixation sites [48]. Self-reinforced P(L/DL)LA plates and screws of 70:30 P(L/DL)LA (BioSorb Fx, BionX Ltd., Bedford, MA, USA) were clinically assessed for bone fixation with minimal post-operative complications [49] in craniomaxillofacial [40] and limb surgery [50]. Self-reinforced PLA was successfully used as fixation plates and screws in the treatment of children's forearm fractures, demonstrating stability in a long arm cast, and supporting osteosynthesis whilst eliminating the need for a second surgery [51].

Polymer blends involve the physical entanglement of at least two polymers in the mix. PLLA has also commonly been combined with PGA for the purpose of bone fixation applications. PGA is a rigid material with high crystallinity, which translates to a high strength and modulus, but also has a faster degradation rate than PLA, on the scale of 6–12 months [52]. When combined with PLLA, a desirable blend with good mechanical properties is formed. PLLA/PGA (82:18) has been used in widespread craniofacial applications due to its ability to maintain sufficient mechanical strength for 6–8 weeks, with in vitro studies showing mass loss being complete in 9–15 months [13]. When PGA is combined with PLA, the copolymer has a balance of the hydrophilic properties of PGA and PLLA, leading to an intermediate rate of hydrolysis. Higher incorporation of PGA may elicit a faster degradation rate, but this is not always the case. One study found that a content of PLA between 75 and 100% and PGA 0–25% was the most desirable in terms of degradation characteristics [14]. Clinically, LactoSorb copolymer pins, composed of PLLA/PGA (82/18) are used in an array of orthopaedic applications [13]. This material has a strength loss profile that better mimics the healing process in comparison the homopolymer PGA or PLLA. A degradation rate slower than that of PGA reduces the occurrence of premature fixation strength loss before bony union occurs, whilst a faster degradation rate than PLLA allows for a faster transfer of load to the surrounding healing tissue, promoting remodelling. The PLLA/PGA pins were used successfully in distal chevron osteotomies, providing fixation on a level comparable with metallic implants [53].

Blending lactide polymers with non-lactide polymers were investigated in order to alleviate the brittle nature of the former materials. Poly-L-lactide/ε-caprolactone (PLCL), trimethylene carbonate (TMC), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) have all shown promise in reducing the brittle character of PLLA specifically. Poly DLlactide/glycolide copolymer (PDLGA) and poly-L-lactide/ε-caprolactone (PLCL) were combined to form a set of PDLGA/PLCL blends. Greater incorporation of PLCL into the blend provided a decline in elastic modulus and yield stress and an increase in yield strain. Characteristics were provided from the elastic polymer, PLCL. When PLCL makes up 60% of the polymer blend, the brittle nature of the polymer is eradicated [19]. A novel terpolymer based on L-lactide, D,L-lactide, and trimethylene carbonate (TMC) displays brilliant mechanical and biocompatibility properties of PLDLA. TMC, an elastomeric component, was incorporated in with the lactide polymers to alleviate the brittle nature. The three components were first copolymerised and then moulded into pins for evaluation. Incorporation of TMC into the blend reduced mechanical properties of the material however make it suitable for use in soft tissue applications [17]. PDLLA was combined with copolymer of trimethylene carbonate (TMC) and e-caprolactone (CL) to form a PDLLA/P(TMC-CL) blend, assessing its suitability for fracture fixation by studying degradation. The material, manipulated into bone plates and screws, was tested in vitro and in vivo (mandibular fractures). In vitro, the initial tensile strength was maintained for a time-period after bone healing occurred at 6–12 weeks. At 45 weeks of the study, it was seen that minimal water was absorbed by the degrading blend, with no observation of significant mass loss. In vivo, the implants devised enabled uneventful bone healing and no premature failure of the devices were seen; however, although undisturbed bone healing occurred around 12 weeks, the implanted screws had broken and bone plates loosened [20]. Inion (Finland) at present has clinically available products on the market that are composed of L-Lactide, D,L-Lactide, polyglycolide, and TMC [54]. Clinical studies using the material in the form of miniplate conclude that the resorbable blend can be used in the same circumstances as titanium miniplate, with exception in maxillary elongation and mandibular setback [55], due to higher relapse in these circumstances and one degradable plate not being stable enough to prevent such an occurrence. Pins composed of PLLA/PHBV were assessed for their mechanical and degradation properties, where the addition of PHBV improved thermal properties and dampened the brittle character of PLLA. Intermediate ratios of the PLLA/PHBV (60/40, 50/50, 40/60) copolymer degraded faster than pure PHBV whilst maintaining mechanical properties for longer than pure PLLA [16].
