Journal of Applied Biomaterials & Biomechanics 2004; 2: 65-73
Coralline hydroxyapatite bone graft substitute: A review of experimental studies and biomedical applications E. DAMIEN, P.A. REVELL Eastman Dental Institute, University College London - UK
ABSTRACT: A review of the various coral bone graft substitutes currently available for experimental and biomedical applications and ongoing investigations of coral derived bone replacement materials is presented here. Natural and synthetic graft materials that have been studied in vitro and in vivo and used in different medical procedures in osseous tissue have focused mainly on freeze-dried bone, hydroxyapatite (HA), tricalcium phosphate (TCP) and coral. Coralline hydroxyapatite (CHA) is manufactured from marine coral, which has a natural trabecular structure similar to that of bone, by the hydrothermal conversion of the calcium carbonate skeleton of coral to hydroxyapatite, a calcium phosphate. While many studies have demonstrated promising biocompatible properties and osteogenic results, as a bone graft substitute and bone void filler, the use of CHA may be limited owing to its inherent mechanical weakness and reduced biodegradation. The benefits of CHA as bone graft are predominantly its safety, biocompatibility and osteoconductivity so that it can be used as a substitution biomaterial for bone in many indications clinically. CHA can also be used as an efficient carrier system for the local delivery of growth factors to enhance osteointegration and implant fixation into peri-implant osseous tissue. (Journal of Applied Biomaterials & Biomechanics 2004; 2: 65-73) KEY WORDS: Biomaterial, Bone graft substitute, Coral, Coralline hydroxyapatite, Implant, Growth factor, Osteoconduction, Osteointegration Received 06/05/03; Revised 29/07/03; Accepted 22/09/03
INTRODUCTION The clinical success of bioinert, bioactive and resorbable implants has been vital to the repair and restoration of the bone. All synthetic biomaterials used for biomedical applications represent a compromise in their survival in the body and a third to half of skeletal prostheses fail within 10 to 25 years necessitating revision surgery. Autogenous bone grafting has been the standard approach to reconstruction of trauma-induced osseous defects, and is used in joint revision surgery but poses the disadvantages related to harvesting, size, shape and availability of autografts. Autologous bone is subject to resorption and sometimes reoperations may be needed to achieve an adequate result. A bone substitute eliminates the need for autoge-
nous and allogeneic bone grafting and the associated complications especially related to the supply of donor bone for harvesting and the transmission of diseases. Synthetic HA has been used extensively in experimental studies and in restoring or augmenting defects in orthopaedic surgery as it is biocompatible and osteoconductive (1-10). Hydroxyapatites of natural origin used in biomedical applications are derived from human or bovine bone or from coral, as found in marine invertebrate life. Hydroxyapatite from natural origins differs from synthetic HA in composition, crystal morphology, size, shape and physico-chemical properties depending on the technology used to obtain the synthetic HA. Synthetic HA can be prepared from an aqueous solution (11), by solid-state reaction (12) or by hydrothermal methods (13). © Società Italiana Biomateriali
1722-6899/065-9$15.00/0
Coralline hydroxyapatite bone graft substitute: A review of experimental studies and biomedical applications
a
b
Fig. 1 - a) Porites species and b) Goniopora species. These under water photographs show the marine corals in their natural habitat.
TABLE I - CLASSIFICATION OF CORALS IN BIOMEDICAL USE Coral taxonomy Kingdom Phylum Order Family Genera
Animalia Coelenterata Scleractenia Poratidae Porites species (Fig. 1a) Goniopora species (Fig. 1b)
Coralline hydroxyapatite, an osteoconductive synthetic bone graft substitute material, is manufactured by the hydrothermal conversion of the calcium carbonate skeleton of coral to hydroxyapatite in the presence of ammonium phosphate preserving the original porous structure which is similar to that of bone. CHA has been investigated extensively at various bone locations in different animal models such as mice (14), rats (15), guinea pigs (16), rabbits (17, 18), dogs (18, 19), mini pigs (20), goats (21), sheep (22), horses (23), and primates (24) as well as in human clinical cases (25-36) to prove its safety, biocompatibility, osteoconductivity as well as its osteogenic potential. 66
Although CHA showed osteoinductive properties in baboons (37) it failed to induce new bone formation in the connective tissue of the palatal papilla in miniature pigs (38) or in the abdominal muscles (39) or in the latissimus dorsi muscle in rats but addition of bone marrow induced bone formation in the rat (40). Human studies have demonstrated excellent results in cosmetic, dental, and reconstructive surgery including fracture reduction, craniomaxillofacial defects, periodontal osseous destruction, ridge augmentation and preservation after tooth extraction, orbital defects as well as fusion of vertebrae (41, 42). These results indicate that the material is immunologically inert from the point of inducing inflammation due to lack of proteins in the processed corals. It is safe to use as a defect filler in low-load applications but is mechanically weak. Although a particulate form is most frequently used because of its versatility, porous granules or block forms are mainly used clinically (43).
TYPES OF CORALS USED AS BONE REPLACEMENT MATERIALS IN BIOMEDICAL APPLICATIONS The species of marine invertebrates exploited in medical applications are identified in Table I. Members of Porites (Fig. 1a) and Goniopora (Fig. 1b) species belonging to the Poratidae family are widely used for developing coralline HA bone substitute.
Damien and Revell
These under water photographs show the marine corals in their natural habitat. Sea corals of Porites species possess anatomical structure, physical, and chemical characteristics that simulate human bone and is biocompatible and osteoconductive as compared and detailed in the references given in Table II (24, 44-47). There are two main types of porous coralline HA differing in microstructure which are used as bone substitutes in biomedical applications (Tab. II).
PREPARATION OF CORALLINE HYDROXYAPATITE FROM THE SKELETON OF CORALS
ming of the coral heads of choice to the desired size and shape prior to screening for the presence of microbes, endotoxins and genotoxins. A simple method of converting the calcium carbonate skeleton of the corals into hydroxyapatite granules has been developed by Sivakumar et al (1996) by subjecting sea corals to a temperature of 900°C so that all organic materials were removed and all carbonate phases were decomposed (49). The preheated coral, calcium carbonate, is converted into hydroxyapatite by chemical exchange reaction with diammonium phosphate under hydrothermal conditions resulting in pure coralline HA powder with
The replamineform process is a technique for the fabrication of porous bone replacement materials in which surface morphology is altered to make a porous material using the microstructure of marine invertebrates as templates. The uniform pore size, controlled pore microstructure ratio and interconnection of pores are protected in porous configuration of coral hydroxyapatite by hydrothermal conversion of the skeleton of natural coral as described by Roy and Linnehan (1974) and Chiroff et al (1975) (13, 48). No evidence of infection, rejection, or encapsulation was seen but uniform new bone growth was found into the pores of replamineform coralline HA as occurred in the basic CaCO3 skeleton of the coral genus Porites when implanted in the trabecular bone of the distal femur and proximal tibia of dogs (48).
DEVELOPMENT OF SEA CORAL FOR BONE GRAFTING The important steps in the preparation of sea coral for bone grafting and coralline hydroxyapatite for bone replacement in clinical situations are given in Figure 2. Coral grafts are prepared after cleaning and trim-
Fig. 2 - General schemes for the development of sea coral for bone grafting.
TABLE II - MICROSTRUCTURE OF CORALS USED IN BIOMEDICAL APPLICATIONS Origin of CHA Genus
Microscopical similarity
Porites
Cortical bone, pore size corresponds to average diameter of an osteon in human bone
Goniopora
Cancellous bone
Total porosity
Closed pore size (µ)
Interconnecting pores (µ)
References
70%
500-600
220-260
67
Coralline hydroxyapatite bone graft substitute: A review of experimental studies and biomedical applications
both aragonite and calcite phases, as was confirmed by powder X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis as demonstrated in Figure 2 (49). 10CaCO3 + 6(NH4)22HPO4 + 2H2O → Ca10(PO4)6(OH)2 + 6(NH4)2CO3 + 4H2CO3 Xu et al (2001) used a mineraliser, KH2PO4, to accelerate the exchange process and to eliminate the formation of intermediary phases (Fig. 2) (50). In the absence of the mineraliser, KH2PO4, aragonite was converted at high temperature and pressure into calcite, which was subsequently converted to βTCP and finally to hydroxyapatite, as HA being the most thermodynamically stable form (50). Whereas in the presence of KH2PO4, the exchange process was completed without the formation of intermediary conversion stages by the direct conversion of aragonite into HA. The advantages of the use of mineraliser also include the enhanced rate of conversion and better retention of the original structure of the coral. The retained interconnectivity of the coral can directly affect the biological properties (50).
COMMERCIALLY AVAILABLE CORALLINE HA FOR MEDICAL PROCEDURES
Different types of commercially available CHA products are given in Table III with an indication of its characteristic feature. Commercial products are available as granules or blocks with 200 µ or 500 µ
pore size. An account of some of their important biological properties are compared and given in the biological evaluation section. Table III shows commercially available coralline HA which are used to replace osseous tissue in surgical procedures in human.
BIOLOGICAL EVALUATION AND CLINICAL INDICATIONS FOR THE USE OF COMMERCIALLY AVAILABLE CHA Interpore-200® and -500® have been reported to be osteoconductive rather than osteoinductive, as new bone formation is found in the pore surfaces which are in direct contact with bone but there is no incorporation of bone into the pores where the implant is not in contact with viable bone. Interpore500® is reported to be the new resorbable version and is available as granules of 0.4-1.0 mm for oral surgical applications and 0.4-6.0 mm for periodontal applications. It has been evaluated for use in atrophic mandibular ridge augmentation and also in bone reconstruction in periodontal sites where rapid vascularisation of the implant material occurred and the newly formed fibrovascular tissue transformed into bone (46, 59-61). Interpore-500® has shown advantages over powdered HA as it demonstrated bioresorbability and the potential to stimulate the development of osseous tissue within the pores of the material demonstrating increased bone bonding and graft fixation (60, 61). Interpore-200® is also available as blocks and granules. Histological data from studies in animals and from human trials in a variety of surgical procedures have
TABLE III - COMMERCIALLY AVAILABLE CORALLINE HA IN MEDICAL USE Product
Details
Biocoral®
99% calcium carbonate
Bio Eye
Original coralline orbital implant
®
Pro-Osteon 200
®
Porous blocks of 200 µ pores Anterior cervical fusion
Pro-Osteon 500®
Porous blocks of 500 µ pores Cervical fusion
Interpore-200®
200 µ pores Granules and blocks Osteoconductive
Interpore-500®
500 µ pores Granules and blocks Osteoconductive Resorbable
68
References 22, 51, 52 53, 54 21, 55 - 57
24, 46-62
Damien and Revell
revealed satisfactory results as shown and referred in Table IV. These implants were well-tolerated with significant amounts of bone infiltration showing no resorption or osteolysis beneath the implant and the material was strong enough to resist denture forces when used in tooth sockets (24, 46, 62). Pro-Osteon 500® is considered as a viable option for the management of bone defects as it showed good osteogenesis in a one year follow up study in distal femur implantation in rabbits (21, 56). The outcome of a clinical study involving the follow up of 71 patients for 2.4 years postoperative, using Pro-Osteon 500® to surgically replace bone tumours was very promising (55). Biocoral®, a coralline calcium carbonate, showed good results as a bone substitute in clinical studies (22, 51). Bio Eye® is the original coralline orbital implant derived from sea coral which showed comparable results with that of available synthetic HA eye implants in several studies (53, 54).
EXPERIMENTAL INVESTIGATIONS TO EVALUATE THE BIOLOGICAL PERFORMANCE OF CHA Calcium phosphate and calcium carbonate biomaterials are widely used as bone substitutes in periodontal surgery. Dual-energy X-ray absorptiometry is considered as an accurate and reproducible method to assess the densities and to monitor bone ingrowth into CHA blocks originated from exoskeletal coral heads of genus Goniopora but not into that originated from genus Porites as demonstrated when implanted in the mandibles and craniums of adult dogs (44). The orientation of the microstructure of coral-derived porous HA influences bone ingrowth as demonTABLE IV - CLINICAL APPLICATIONS CORALLINE HA
INVOLVING
CHA Clinical applications Indications Craniomaxillofacial augmentation Orbital implants Spinal fusion Void filler in areas of bone loss by trauma or tumour Drug-delivery device Podiatric surgery Fracture reduction
References
25, 72 29, 33, 53, 54, 73 21, 41, 74-77 30, 55 74 78 42, 71, 79
strated by implanting CHA discs (25 mm diameter) of two distinct geometric configurations, prepared by cutting the corallites either longitudinally or transversally, into calvarial defects of baboons (63). Coralline HA has been reported as a biocompatible, osteoconductive osteogenic bone graft ceramic which showed evidences of bone remodelling in the bone ingrowth (64 - 68). The degradation rate needs to be equal to the rate of tissue regeneration to achieve optimum results during implantation. CHA has shown varying rates of biodegradation and resorption in different studies (48, 69, 70).
STUDIES USING CHA IN CLINICAL SURGICAL PROCEDURES
Loss of bone volume as a result of either trauma or osteoporosis in maxillofacial bone has been compensated for by autologous onlay or subperiosteal apposition grafts of synthetic materials. Calcium phosphate or calcium carbonate biomaterials are widely used as bone substitute in surgery (Tab. III and IV). CHA has been extensively used clinically as a bone substitute to fill bone defects in human oncology cases (55), fracture reduction procedures (42), and anterior lumbar inter body fusions as given in Table IV (41). Coralline HA blocks were successfully used as bone graft at the calcaneocuboid joint to achieve distraction in a calcaneal fracture (71). The grafted sites always had at least as much bone growth as control sites, never any less.
ENHANCEMENT OF OSTEOINTEGRATION OF CHA Coral for delivery of biological molecules to promote bone regeneration Very few studies have been performed to investigate enhancement of osteointegration of CHA by stimulating local tissue regenerations using growth factors that activate the cells in the microenvironment of the implant. Synergistic combinations of hydroxyapatite biomaterials and biomolecules such as bone morphogenetic protein 2 (BMP 2), Transforming growth factor (TGF β), Insulin like growth factors I (IGF I), IGF II, and other factors present in the mineralised bone matrix have been tried (8082). These factors have important regulating roles in bone healing and (re)modelling, due to their potent effects on osteoblast function, as part of autocrine/paracrine mechanisms to initiate and promote the development of bone. The cells produce additional growth factors that can stimulate osteoblasts, to proliferate and to regenerate bone (83, 84). When a bone defect was filled using synthetic 69
Coralline hydroxyapatite bone graft substitute: A review of experimental studies and biomedical applications
porous HA pretreated with IGF I or IGF II there was rapid regeneration of bone along the HA struts which reconstructed the bone architecture at the site of repair in rabbit femur (85, 86). Both osteoconduction and osteogenesis occur as a consequence of enhanced peri-implant tissue responses. Such rapid repair of bone requires proliferation as well as differentiation of osteoblasts. These osteoblasts synthesize extracellular matrix that is capable of mineralising to become bone (2, 85, 86). CHA discs were used in mice as an ideal local delivery system for BMP with collagen type IV (14). Calvarial and mandibular critical-size defects in rabbits implanted with CHA combined with rhBMP 2 were completely replaced by bone at 12 weeks to the formation of a large amount of fibrous tissue and little new bone in the control CHA alone (87). These composite bone substitutes may be ideal materials for repairing various bone defects in the craniomaxillofacial region with enhanced results. Enhancement of new bone formation and an increase in the rate of healing has been noted in rabbit cranial defects filled with CHA composite with demineralised bone matrix (88). Autologous growth factor concentrate (AGF), prepared by ultraconcentration of platelets, contains multiple growth factors and has a chemotactic and mitogenic effect on mesenchymal stem cells and osteoblasts. When AGF was used with coral and CHA, the clinical outcome of posterior fusions and intradiscal fusions of the spine were improved (74). Blocks of HA, natural coral and CHA, implanted in the latissimus dorsi muscle of rats with marrow showed bone formation, demonstrating osteoinduction of CHA implants containing bone marrow which was significantly higher in coral than in CHA (40). At 12 weeks, coral resorbed quickly and lost its compressive strength, which was originally higher than that of HA but bone ingrowth seemed to maintain the mechanical strength of the coral implant which was comparable to that of cancellous bone despite the fact that the implant was resorbing (89).
IMPROVEMENT OF MECHANICAL STRENGTH OF ENHANCE CLINICAL RESULTS
CHA TO
CHA derived from the exoskeleton of the coral genus Goniopora (CHAG) has been shown to be as an efficient scaffold for bone ingrowth. However, although the large pores in the material result in low compressive strength (Tab. I), microcoating the internal surfaces of CHAG with dilactic-polyactic acid (DL-PLA) improves compressive strength, stiffness, and energy absorption. Bone ingrowth and direct appositional growth of new bone were enhanced when DL-PLA coated CHAG was 70
implanted transcortically in rabbit tibial diaphysis compared with uncoated CHAG (90). Coated specimens were not significantly different from canine tibial cancellous bone in strength and stiffness (91).
FUTURE RESEARCH: TISSUE ENGINEERING Progenitor cells can be seeded onto modified resorbable coralline scaffolds to provide a more biologically based method for the repair and regeneration of hard tissue. The patients own healthy cells can be grown inside coral or coralline hydroxyapatite implants outside the body and become differentiated and mimic naturally occurring tissues. These tissue-engineered constructs can be implanted into the patients to replace diseased or damaged tissues. As the scaffolds are resorbed they will be replaced by host tissues with viable blood and nerve supply. There are important economical advantages to these approaches as the natural coral resources can be effectively utilised. The search for the ideal coralline product should be based on the strict pursuit of the recommended surgical guidelines and techniques for each specific indication, understanding the limitations of the material. Patient selection is extremely important in selecting a graft material. The ideal coralline graft substitute material will be a stable, compatible, (non)resorbable coralline implant which induces bone formation. “Coral/coralline HA + progenitor cells + biological molecules” will be the answer to the future problem of the ever increasing demand for a safe, biocompatible, effective, readily available and economical bone substitute material to replace damaged or lost bone in trauma or diseased bone in the aging population. Research will continue providing badly needed long-term experimental and clinical outcome data and histological evaluations, permitting a more informed choice to be made. New applications are evolving, such as coating metal implant surfaces with CHA and combining this material with purified collagen or osteogenic factors to enhance new bone formation and osteointegration.
ACKNOWLEDGEMENTS The authors would like to acknowledge Drs Rosdan S and Samsudin AR for help with the figures and Miss Damien CS for assistance with the manuscript preparation.
No benefit of any kind will be received either directly or indirectly by the authors.
Damien and Revell Address for correspondence: Dr. Elsie Damien Biomaterials and Tissue Engineering Eastman Dental Institute University College London 256 Grays Inn Road London, WC1X 8LD - UK
[email protected]
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