Ординатура / Офтальмология / Английские материалы / Biomaterials and regenerative medicine in ophthalmology_Chirila_2010

484 Biomaterials and regenerative medicine in ophthalmology

ePTFE is no exception. There have been cases of secondary complications and infections are not unknown (Daniel, 1994; Mercandetti, 2008). It is not always obvious why products are withdrawn from the market and clearly clinical efficacy based on sound scientific principle and research is the priority; however, it is a long and winding road from laboratory-based research to the development of new biomaterials to commercial realisation. Modification of successful and approved materials makes sense both from a research and a commercial point of view, so hopefully the final chapter in the ePTFE story is yet to be written (Mercandetti, 2008).

18.5.5 High density polyethylene

PE is another polymer that has made a very successful transition from the laboratory to industrially oriented applications to biomedical applications. Different medical applications require one of the typically commercially available grades: low density PE (LDPE), HDPE and ultra high molecular weight PE (UHMWPE). Each grade has different properties (e.g. mechanical), which render them more or less suitable for different applications; for example, load-bearing orthopaedic applications use UHMWPE, craniofacial repairs use HDPE and porous HDPE (PHDPE). The higher tensile strength of HDPE compared with LDPE is advantageous in facial reconstruction (Bikhazi and Van Antwerp, 1991; Wellisz, 1993). HDPE is somewhat more difficult to sculpt than SAM and tends to form a thin fibrous in-growth layer which stabilises the implant; the downside is that, in the event of revision surgery, subsequent removal becomes more difficult. Importantly, the drilling and fixation techniques, which are mandatory in so many orbit reconstructions, do not fracture HDPE (Eppley, 2003a). The extremely useful and welltested porous form, PHDPE, is found in the MedPor® range of products (Porex Surgical Inc., GA, USA). Incidentally, this manufacturer has a most informative and helpful website for their products (Porex Corporation, 2008). In a recent review, Lee et al. report on a retrospective analysis of 170 patients ‘to determine the safety and efficacy of using PHDPE in the repair of orbital defects’. They concluded that it was so successful, and overall outcomes were so positive, that it has now been adopted as part of their clinical practice.

This also eliminates potential problems associated with donor site morbitity (Lee et al., 2005). According to Eski et al., the best clinical outcomes using PHDPE are found for mild to moderate zygomatico-orbital fractures (Eski et al., 2007). However, revision surgery cannot be ruled out in cases requiring complex repair and restoration procedures, and Antonopoulous et al. report the successful use of Medpor® in revision surgery of an ‘enormous composite defect’ after an initial reconstruction using cement had failed (Antonopoulous et al., 2006). After a 2-year follow-up, no infection was observed and the cosmetic outcome was described as ‘satisfactory’. This is just one case that

highlights some of the challenges and choices (discussed in the introduction) in the selection of suitable materials. PE in its various forms is one of the most successful and oft-cited biomaterials used in orbital reconstruction: its future appears secure.

18.5.6 Bone cements

It is difficult to discuss bone cements without reference to orthopaedic and, to a lesser extent, dental applications. However, despite the warning in the Introduction that care must be taken not to ‘mindlessly adopt’ orthopaedic materials and methods, it is for applications in these areas that bone cements have been largely developed. In craniofacial applications bone cements are generally used in conjunction with a variety of other repair materials. Hence, Donkerwolcke’s general review on ‘Tissue and bone adhesives – historical aspects’ is a useful introduction (Donkerwolcke et al., 1998). In his ‘State of the art review’, Lewis points out that the success of the two-part selfpolymerising PMMA system is such that it is now generally known as ‘bone cement’. Although primarily focused on orthopaedic applications, this system is included because of its probable general interest (Lewis, 1997).

Acrylic and methacrylic-based polymeric materials are made from either acrylic or methacrylic acids or their esters. The best-known example, PMMA, was developed for use in dentistry in the 1930s and soon became popular in orthopaedic applications. In 1944, Blum reported the use of ‘acrylic dough’ in spinal fixations and for the repair of skull defects in animals (Blum, 1944). In the 1950s cold-curing acrylic cements became available. The pioneering English orthopaedic surgeon Sir John Charnley, who developed and gave his name to the hip replacement device, worked in collaboration with industry to develop bone cement in 1958 (Charnley, 1960). However, ‘cranioplasty’ applications soon became just as frequent (Prolo, 1985). Eppley gives a useful discussion on the advantages and limitations of PMMA (Eppley, 2003a). The latest generation of bone cements are more custom-designed to be used for specific applications. Generally, they are antibiotic-loaded to reduce the risk of infection in both primary and revision operations.

In a review in 1999, the degradable calcium phosphate cements were predicted to be the ‘new technology’ in craniofacial surgery and maxillofacial reconstruction in the new century (Schmitz et al., 1999). A carbonated apatite cement was used in a series of cranio-maxillofacial cases including ‘post-traumatic bone defects in the orbital, periorbital and malar regions’ (Wolff et al., 2004). No adverse effects were found after a mean follow-up period of 29 months, no inflammation was reported and the conclusion was that this was a suitable material for treating moderate-sized defects. Adverse effects, however, have been reported in other applications. Burstein et al. have compared the use of two forms of hydroxyapatite cements in craniofacial

486 Biomaterials and regenerative medicine in ophthalmology

(including orbit) reconstruction. In their first study they used a granular form and described how most of the complications manifested themselves after the first 18 months (Burstein et al., 1997). In a subsequent pioneering study of 61 patients (56 of whom were children) they used a powdered form of the hydroxyapatite cement and reported greatly improved clinical handling and results. This paper is impressive in its honesty in so far that the authors report that some of the complications subsequently observed were due to their ‘inexperience during their early use of [hydroxyapatite] HAP cements’. This paper illustrates clearly the learning curve facing surgeons when first using materials that are new to the market (Burstein et al., 1999).

18.5.7 Polyurethanes

Polyurethane-based materials have a long history of use as biomaterials. Their good biocompatibility as well as excellent strength have seen them used in a wide variety of biomedical implants and devices such as cardiac pacemakers and vascular grafts. Like many biomaterials, however, their development involved some less than successful products. As described in a review by Donkerwolke et al., their use as bone glues, particularly in orthopaedic applications, dates back to the 1950s and 1960s (Donkerwolcke et al., 1998). In 1958, Manderino and Salvatore (1959) announced the use of a polyurethane polymer as a bone glue or cement. It was described in Time magazine in 1959 as ‘the realisation of a dream’ but unfortunately with time the reality did not live up to that dream. Later, both animal and human studies showed a plethora of infections and the formation of a fibrotic, non-adhesive layer. However, the overall good biocompatibility as well as the excellent strength of polyurethane polymers has seen them used in a wide variety of biomedical implants, including cardiac pacemaker leads and catheters (Gunatillake and Adhikari, 2003).

This later success of polyurethane-based devices has sparked some interest in producing biodegradable polyurethanes. This is usually achieved through the coupling of degradable prepolymers with urethane linkages. A diisocyanate can be used to create a urethane linkage with a degradable hydroxy-terminated polyester to create a poly(ester-urethane) (Fig. 18.5). This approach enables chain-extended and cross-linked materials (if a triisocyanate is used) to be easily synthesised. Using such procedures makes it possible to control and modify the degradation rate and hence control the reduction in mechanical strength (Seppälä et al., 2004). These advances in the control of properties that are critical in facial repair and reconstruction may open up the possibility of future commercial development of polyurethanes for a wider range of applications.

O

( O ( R )m O C NH R′

O NH C

(n

components already present in tissues, biocompatibility and integration would be expected to be enhanced. Unfortunately, the polymers of natural origin generally do not perform as well as expected. In order to produce enough material for the scaffold, the crude polymer is usually sourced from a different species to the patient. As a result, there is concern regarding not only disease transmission, but also the variable quality of these polymers, which often differs between batches. Furthermore, for many of these natural polymers, the mechanical properties of the processed products are less than ideal.

Natural polymers obtained from non-animal sources may overcome some of the disadvantages discussed above. Polyhydroxyalkanoates (PHAs) are polyesters that are produced by micro-organisms and degrade via hydrolysis of the ester linkages. The most commonly studied PHAs for biomedical applications are poly(3-hydroxybutyrate) (PHB), poly(3-hydroxyvalerate) (PHV) and poly(3-hydroxyhexanoate) (PHHx), and their copolymers. A drawback of the use of PHAs in biomedical devices is their limited availability and the often time-consuming extraction techniques necessary. Undesirable endotoxins are sometimes incorporated by the polymer-synthesising bacteria colonies, hence there is some concern over their use as implant materials.

The structures of these homopolymers are shown in Fig. 18.6.

18.6.3 Polylactones: introduction

Due to their good biocompatibility and ability to bioresorb, polylactones – such as polylactide (PLA), polyglycolide (PGA), poly(ε-caprolactone) (PCL) (Fig. 18.7) – and their copolymers have been studied for biomedical purposes since the 1960s (Albertsson and Varma, 2003). The first commercially available product, launched in 1962, was a polyglycolide suture, DexonTM (Tyco Healthcare Group, CT, USA) (Albertsson and Varma, 2003). Poly(lactide- co-glycolide) (PLGA) sutures became available a few years later. The latest generation of sutures uses other polylactones acids) and incorporates factors such as antibacterials. Commercially available products such as MonocrylTM Plus Antibacterial is a glycolide/ε-caprolactone copolymer (poliglecaprone 25)

(c)

18.7Structures of (a) PLA, (b) PGA and (c) PCL.

(Johnson & Johnson Gateway). The advantage of such composite polymers is that they not only combine some of the advantages of each component, but they also often make it possible to tailor the various properties (mechanical and/or degradative).

18.6.4 Poly(lactide-co-glycolide) polymers

Lactosorb SE®, one of the most successful materials used in maxillo and craniofacial applications, became available commercially in 1996. It is a copolymer of l-lactic acid (82%) and glycolic acid (18%) and, although it has a specific strength comparable with titanium, it degrades in vivo within 12 months. LactoSorb SE® overcame many of the limitations encountered with earlier bone substitutes such as with the permanent PTFE-based Proplast® series (mouldability, delamination, fragmentation and trans-cranial migration) discussed earlier. With respect to orbit repair, the most common LactoSorb SE® devices used are bone fixation devices such as sutures, microand mini-plates, and screws.

In 1996, Eppley reviewed the obstacles and ‘potential role’ of resorbable plates and screws in cranio-maxillofacial trauma (Eppley et al., 1996). In 1997, he observed that ‘favourable clinical experiences have been very limited’, although that same year Kumar et al. reviewed their use in 22 paediatric cases (Eppley and Prevel, 1997; Kumar et al., 1997). However, Kumar recognised that ‘further experience using this technology’ would be required before it could be adopted as ‘the standard of care’ in infants. In 2005, Eppley again reviewed the use of resorbable plates and screws in paediatric fractures (Eppley, 2005). Although a pilot study using them in large orbital wall repairs appeared in 1996, it was not until 2007 that a specific reference to an orbital rim repair using a resorbable plate appeared. ‘An excellent cosmetic and functional outcome’ was reported by Curtis et al. in a complicated case involving both a corticocancellous bone graft and the biosorbable plate to treat a rare intraosseous hemangioma (Al-Sukhun et al., 2006; Curtis and Zoellner, 2007).

490 Biomaterials and regenerative medicine in ophthalmology

Polymeric materials, including PLA–PGA copolymers, with tailored properties are feasible in the laboratory at least. For biomedical applications, such polyesters are usually synthesised by ring opening polymerisation reactions. Unlike the condensation polymerisation of monomeric lactic acid, the ring opening approach can produce polymers of high molecular weight. Under certain conditions the polymerisation is living and proceeds in a controlled fashion yielding a narrow molecular weight distribution. In such systems, the molecular weight and, consequently, the physical properties of the polymer can be controlled easily by the ratio of monomer to initiator. Block copolymers can be synthesised by the addition of a second monomer after the polymerisation of the first monomer is complete. Molecular weight is related to bioresorption and biodegradation, hence – in theory at least – devices could be produced for very specific applications, such as orbital rim repair. In practice, such a finely tailored range of products is seldom commercially available. Since these synthetic polymers have had US Food and Drug Administration (FDA) and Therapeutic Goods Administration (TGA) (Australia) approval for nearly 50 years, as well as being already used in a range of craniofacial applications, they clearly lend themselves to further laboratory-based research with a view to extending commercial interest and development of new products.

As mentioned previously, there is no perfect polymeric repair material and in this case there is some concern regarding the release of acidic degradation products and the negative effect this can have at the implant site. It is argued that, although the degradation products can be eliminated from the body via well-understood metabolic pathways, since the PLLA undergoes bulk degradation there is a burst release of a high concentration of acidic by-products that can be entrapped inside the polymer material. This lowers the local pH and can trigger an inflammatory response. The surface of these polymers is generally considered to be less than ideal for interacting with the biological environment because of a lack of suitable functional groups (Suh et al., 2001). Consequently, many studies have been directed towards overcoming this through surface modification of the polyesters. Attachment of biologically active molecules, such as silk fibroin and type I atelocollagen has been shown to have a favourable effect on osteoblast cell behaviour in vitro (Cai et al., 2002; Suh et al., 2001).

If polylactones and other polymers are to be made more attractive clinically, then the ability to tailor their properties is essential, not only for promoting initial bone formation, but also for controlling the degradation rate and subsequent loss in mechanical properties. This is important not only for device stability but for the remodelling of the new and surrounding bone needed to ensure full restoration of bone function at the defect site.

18.7The future: composite materials, bone regeneration and tissue engineering

New materials are constantly being developed. Although their immediate application may be in areas far removed from the medical arena, as discussed in this chapter, they do often eventually find use as biomaterials. Fundamental research on the surface modification of materials will continue to make an important contribution. Another trend is the merging of material science with biology and pharmacology to introduce antibacterials, antibiotics and growth factors in order to produce ‘activated’ biomaterials. Although this chapter is limited to polymeric materials and did not cover ceramics or metals, it should be mentioned that there are some interesting reports on the development of composite materials that combine polymers with other alloplastic compounds. Of particular relevance for craniofacial reconstruction is that of a polymer and a bioactive ceramic such as hydroxyapatite or tricalcium phosphate (TCP). This approach is not new, of course, but in spite of some major challenges, one of which is achieving the right chemical or physical binding between the two materials, a range of bone repair composite materials has reached both the commercialisation and clinical stages. These materials were developed by an interdisciplinary group at the National University of Singapore (Hutmacher et al., 2007). Both polycaprolactone/hydroxyapatite and poly(ε-caprolactone/ TCP scaffolds were used in orbital floor reconstruction with good clinical outcomes after 12 months.

Hopefully, some of the fundamental research advances being made in developing new materials, hybrid/composite materials and tissue-engineered constructs will translate into some exciting new biomaterials for use in complex and demanding orbital repair and reconstruction applications.

18.8References

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