Sergey V. Dorozhkin

Biological and Medical Significance of Calcium Phosphates

The inorganic part of hard tissues (bones and teeth) of mammals consists of calcium phosphate, mainly of apatitic structure. Similarly, most undesired calcifications (i.e. those appearing as a result of various diseases) of mammals also contain calcium phosphate. For example, atherosclerosis results in blood-vessel blockage caused by a solid composite of cholesterol with calcium phosphate. Dental caries result in a replacement of less soluble and hard apatite by more soluble and softer calcium hydrogenphosphates. Osteoporosis is a demineralization of bone. Therefore, from a chemical point of view, processes of normal (bone and teeth formation and growth) and pathological (atherosclerosis and dental calculus) calcifications are just an in vivo crystallization of calcium phosphate. Similarly, dental caries and osteoporosis can be considered to be in vivo dissolution of calcium phosphates. On the other hand, because of the chemical similarity with biological calcified tissues, all calcium phosphates are remarkably biocompatible. This property is widely used in medicine for biomaterials that are either entirely made of or coated with calcium phosphate. For example, self-setting bone cements made of calcium phosphates are helpful in bone repair and titanium substitutes covered with a surface layer of calcium phosphates are used for hip-joint endoprostheses and tooth substitutes, to facilitate the growth of bone and thereby raise the mechanical stability. Calcium phosphates have a great biological and medical significance and in this review we give an overview of the current knowledge in this subject.

Bioceramics of calcium orthophosphates.

A strong interest in use of ceramics for biomedical applications appeared in the late 1960s. Used initially as alternatives to metals in order to increase a biocompatibility of implants, bioceramics have become a diverse class of biomaterials, presently including three basic types: relatively bioinert ceramics, bioactive (or surface reactive) and bioresorbable ones. Furthermore, any type of bioceramics could be porous to provide tissue ingrowth. This review is devoted to bioceramics prepared from calcium orthophosphates, which belong to the categories of bioresorbable and bioactive compounds. During the past 30-40 years, there have been a number of major advances in this field. Namely, after the initial work on development of bioceramics that was tolerated in the physiological environment, emphasis was shifted towards the use of bioceramics that interacted with bones by forming a direct chemical bond. By the structural and compositional control, it became possible to choose whether the bioceramics of calcium orthophosphates was biologically stable once incorporated within the skeletal structure or whether it was resorbed over time. At the turn of the millennium, a new concept of calcium orthophosphate bioceramics, which is able to regenerate bone tissues, has been developed. Current biomedical applications of calcium orthophosphate bioceramics include replacements for hips, knees, teeth, tendons and ligaments, as well as repair for periodontal disease, maxillofacial reconstruction, augmentation and stabilization of the jawbone, spinal fusion and bone fillers after tumor surgery. Potential future applications of calcium orthophosphate bioceramics will include drug-delivery systems, as well as they will become effective carriers of growth factors, bioactive peptides and/or various types of cells for tissue engineering purposes.

Calcium Orthophosphates in Nature, Biology and Medicine

The present overview is intended to point the readers’ attention to the important subject of calcium orthophosphates. These materials are of the special significance because they represent the inorganic part of major normal (bones, teeth and dear antlers) and pathological (i.e. those appearing due to various diseases) calcified tissues of mammals. Due to a great chemical similarity with the biological calcified tissues, many calcium orthophosphates possess remarkable biocompatibility and bioactivity. Materials scientists use this property extensively to construct artificial bone grafts that are either entirely made of or only surface-coated with the biologically relevant calcium ortho-phosphates. For example, self-setting hydraulic cements made of calcium orthophosphates are helpful in bone repair, while titanium substitutes covered by a surface layer of calcium orthophosphates are used for hip joint endoprostheses and as tooth substitutes. Porous scaffolds made of calcium orthophosphates are very promising tools for tissue engineering applications. In addition, technical grade calcium orthophosphates are very popular mineral fertilizers. Thus ere calcium orthophosphates are of great significance for humankind and, in this paper, an overview on the current knowledge on this subject is provided.

Nanosized and nanocrystalline calcium orthophosphates

Recent developments in biomineralization have already demonstrated that nanosized crystals and particles play an important role in the formation of hard tissues of animals. Namely, it is well established that the basic inorganic building blocks of bones and teeth of mammals are nanosized and nanocrystalline calcium orthophosphates in the form of apatites. In mammals, tens to hundreds nanocrystals of a biological apatite have been found to be combined into self-assembled structures under the control of bioorganic matrixes. Therefore, application and prospective use of the nanosized and nanocrystalline calcium orthophosphates for a clinical repair of damaged bones and teeth are also well known. For example, greater viability and better proliferation of various types of cells have been detected on smaller crystals of calcium orthophosphates. Thus, the nanosized and nanocrystalline forms of calcium orthophosphates have great potential to revolutionize the hard tissue-engineering field, starting from bone repair and augmentation to controlled drug delivery systems. This paper reviews the current state of art and recent developments of various nanosized and nanocrystalline calcium orthophosphates, starting from synthesis and characterization to biomedical and clinical applications. The review also provides possible directions for future research and development.

Amorphous calcium (ortho)phosphates.

Amorphous calcium phosphates (ACPs) represent a unique class of biomedically relevant calcium orthophosphate salts, having variable chemical but essentially identical glass-like physical properties, in which there is neither translational nor orientational long-range ordering of the atomic positions. Normally, ACPs are the first solid phases, precipitated after a rapid mixing of aqueous solutions containing ions of Ca(2+) and PO₄³⁻; however, other production techniques are known. Interestingly, ACPs prepared by wet-chemical techniques were found to have a relatively constant chemical composition over a relatively wide range of preparation conditions, which suggests the presence of a well-defined local structural unit, presumably with the structure of Ca₉(PO₄)₆ - so-called Posner cluster. However, the presence of similar clusters in ACPs produced by other techniques remains uncertain. All ACPs are thermodynamically unstable compounds and, unless stored in dry conditions or doped by stabilizers, spontaneously tend to transform to crystalline calcium orthophosphates, mainly to calcium apatites. This solution instability of ACPs and their easy transformation to crystalline phases are of a great biological relevance. Specifically, the initiating role ACPs play in matrix vesicle biomineralization raises the importance of ACPs from a mere laboratory curiosity to that of a key intermediate in skeletal calcification. In addition, due to significant chemical and structural similarities with calcified mammalian tissues, as well as excellent biocompatibility and bioresorbability, all types of ACPs are very promising candidates for the manufacture of artificial bone grafts. This review summarizes the current knowledge on the occurrence, preparation, composition, structure, major properties and biomedical applications of ACPs. To assist readers in looking for the specific details on ACPs, a great number of references have been collected and systematized.

Calcium orthophosphate-based biocomposites and hybrid biomaterials

In this review article, the state-of-the-art of calcium orthophosphate-based biocomposites and hybrid biomaterials suitable for biomedical applications is presented. This subject belongs to a rapidly expanding area of science and research, because these types of biomaterials offer many significant and exciting possibilities for hard tissue regeneration. Through the successful combinations of the desired properties of matrix materials with those of fillers (in such systems, calcium orthophosphates might play either role), innovative bone graft biomaterials can be designed. The review starts with an introduction to locate the reader. Further, general information on composites and hybrid materials including a brief description of their major constituents are presented. Various types of calcium orthophosphate-based bone-analogue biocomposites and hybrid biomaterials those are either already in use or being investigated for various biomedical applications are then extensively discussed. Many different formulations in terms of the material constituents, fabrication technologies, structural and bioactive properties, as well as both in vitro and in vivo characteristics have been already proposed. Among the others, the nano-structurally controlled biocomposites, those with nanosized calcium orthophosphates, biomimetically fabricated formulations with collagen, chitin and/or gelatin, as well as various functionally graded structures seem to be the most promising candidates for clinical applications. The specific advantages of using calcium orthophosphate-based biocomposites and hybrid biomaterials in the selected applications are highlighted. As the way from a laboratory to a hospital is a long one and the prospective biomedical candidates have to meet many different necessities, the review also examines the critical issues and scientific challenges that require further research and development.

Biphasic, triphasic and multiphasic calcium orthophosphates.

Biphasic, triphasic and multiphasic (polyphasic) calcium orthophosphates have been sought as biomaterials for reconstruction of bone defects in maxillofacial, dental and orthopedic applications. In general, this concept is determined by advantageous balances of more stable (frequently hydroxyapatite) and more resorbable (typically tricalcium orthophosphates) phases of calcium orthophosphates, while the optimum ratios depend on the particular applications. Therefore, all currently known biphasic, triphasic and multiphasic formulations of calcium orthophosphate bioceramics are sparingly soluble in water and, thus, after being implanted they are gradually resorbed inside the body, releasing calcium and orthophosphate ions into the biological medium and, hence, seeding new bone formation. The available formulations have already demonstrated proven biocompatibility, osteoconductivity, safety and predictability in vitro, in vivo, as well as in clinical models. More recently, in vitro and in vivo studies have shown that some of them might possess osteoinductive properties. Hence, in the field of tissue engineering biphasic, triphasic and multiphasic calcium orthophosphates represent promising biomaterials to construct various scaffolds capable of carrying and/or modulating the behavior of cells. Furthermore, such scaffolds are also suitable for drug delivery applications. This review summarizes the available information on biphasic, triphasic and multiphasic calcium orthophosphates, including their biomedical applications. New formulations are also proposed.

Nanodimensional and Nanocrystalline Apatites and Other Calcium Orthophosphates in Biomedical Engineering, Biology and Medicine

Recent developments in biomineralization have already demonstrated that nanosized particles play an important role in the formation of hard tissues of animals. Namely, the basic inorganic building blocks of bones and teeth of mammals are nanodimensional and nanocrystalline calcium orthophosphates (in the form of apatites) of a biological origin. In mammals, tens to hundreds nanocrystals of a biological apatite were found to be combined into self-assembled structures under the control of various bioorganic matrixes. In addition, the structures of both dental enamel and bones could be mimicked by an oriented aggregation of nanosized calcium orthophosphates, determined by the biomolecules. The application and prospective use of nanodimensional and nanocrystalline calcium orthophosphates for a clinical repair of damaged bones and teeth are also known. For example, a greater viability and a better proliferation of various types of cells were detected on smaller crystals of calcium orthophosphates. Thus, the nanodimensional and nanocrystalline forms of calcium orthophosphates have a great potential to revolutionize the field of hard tissue engineering starting from bone repair and augmentation to the controlled drug delivery devices. This paper reviews current state of knowledge and recent developments of this subject starting from the synthesis and characterization to biomedical and clinical applications. More to the point, this review provides possible directions of future research and development.

Calcium Orthophosphate Cements and Concretes

In early 1980s, researchers discovered self-setting calcium orthophosphate cements, which are a bioactive and biodegradable grafting material in the form of a powder and a liquid. Both phases form after mixing a viscous paste that after being implanted, sets and hardens within the body as either a non-stoichiometric calcium deficient hydroxyapatite (CDHA) or brushite, sometimes blended with unreacted particles and other phases. As both CDHA and brushite are remarkably biocompartible and bioresorbable (therefore, in vivo they can be replaced with newly forming bone), calcium orthophosphate cements represent a good correction technique for non-weight-bearing bone fractures or defects and appear to be very promising materials for bone grafting applications. Besides, these cements possess an excellent osteoconductivity, molding capabilities and easy manipulation. Furthermore, reinforced cement formulations are available, which in a certain sense might be described as calcium orthophosphate concretes. The concepts established by calcium orthophosphate cement pioneers in the early 1980s were used as a platform to initiate a new generation of bone substitute materials for commercialization. Since then, advances have been made in the composition, performance and manufacturing; several beneficial formulations have already been introduced as a result. Many other compositions are in experimental stages. In this review, an insight into calcium orthophosphate cements and concretes, as excellent biomaterials suitable for both dental and bone grafting application, has been provided.

A review on the dissolution models of calcium apatites

Eight dissolution models of calcium apatites (both fluorapatite and hydroxyapatite) were drawn from the previously published material and analysed. Limitations and drawbacks each of the model were discussed in details. The models were shown to deal with different aspects of apatite dissolution and none of them was able to describe the dissolution process in general. However, an attempt to combine the data obtained by different researchers made in this paper has resulted in creation of the general mechanism of apatite dissolution. For this purpose, eight models were assumed to complement each other and provide the correct description of the specific aspects of apatite dissolution. The general mechanism for the first time considered all the dissolution stages involved and pointed out to some missing and unclear phenomena to be experimentally studied and verified in future.