The World Health Organisation (WHO) states that musculoskeletal conditions and injuries are the second largest contributor to disability worldwide  which in turn demands for better solutions to repair and replace damaged bone.
Human bone is made of 70% calcium phosphate (CaP) mineral, making it the natural choice as an artificial bone substitute. Ever since the first successful use of CaP was reported in 1920  biomaterial scientists around the world have been on a quest for optimising its properties in order to recreate the perfect man-made bone for orthopaedic and dental applications.
Bone is the perfect natural material. It is a multilevel hierarchically organised composite that consists of 70% inorganic– and 30% organic matter. Due to the challenges posed by replicating the complex mineralization processes that give origin to such a complex structure in a technical setting, materials scientists and engineers have had to come up with their own practical pathways to produce CaPs that would be worthy substitutes of its biological counterpart.
It is important to mention that the failure to replicate the intricate architecture of bone, including its organic components, results in poor mechanical properties, which is one of the main limitations of synthetic CaPs.
CaP refers to a family of compounds, which contain calcium and phosphorus in ratios varying from 0.5 to 2.0. Hydroxyapatite, which has a Ca/P ratio of 1.67, is perhaps one of the most well known members of this family. Its biological form, also known by its mineral name, dahllite, is characterised by its poor crystallinity and the presence of small amounts of carbonate, sodium, strontium and magnesium substitutions, which replace hydroxide, orthophosphate, and calcium in the structure .
The synthetic CaPs used in many commercial products become part of the so-called third-generation biomaterials, which are designed to stimulate specific cellular responses at the molecular level, in part, by being both bioactive and resorbable .
The International Organisation for Standardisation (ISO) defines bioactivity as: “property that elicits a specific biological response at the interface of the material, which results in the formation of a bond between tissue and material” . Tuning bioactivity is not an easy task; however, some synthetic CaPs have been shown to be both bioactive and resorbable. This combination of properties makes the perfect recipe for a material that triggers a positive host response and can in turn be progressively replaced by newly formed bone while retaining an acceptable degree of mechanical stability as required by the application.
In general, many physical forms of CaPs can be prepared via low temperature methods, such as precipitation in aqueous solutions, or via high temperature processing, such as ceramic sintering or solid-state reactions. The broad spectrum of bone diseases and injuries that require bone substitutes materials takes advantage of the multiplicity of physical forms in which CaP can be produced, for example: nanostructured CaPs, powders, granules, coatings, cements and even bulk 3D-printed macrostructured implants for treating large orthopaedic defects.
Phases and applications
The CaP phases of biomedical interest are :
- Monobasic calcium phosphate monohydrate (MCPM)
- Dicalcium phosphate anhydrous (DCPA)
- Dibasic calcium phosphate dihydrate (DCPD)
- α-tricalcium phosphate (α-TCP)
- β-tricalcium phosphate (β-TCP)
- Calcium deficient hydroxyapatite (CDHAp)
- Hydroxyapatite (HAp)
- Octacalcium phosphate (OCP)
- Tetracalcium phosphate (TTCP)
- Amorphous calcium phosphate (ACP)
In medicine and dentistry, the above-mentioned materials are not only used by themselves or in bi- or multiphasic combinations, but also function as precursors in reactive product formulations called CaP (bone) cements that once are implanted in the patient, intend to fixate, stabilise and trigger a positive response of self-healing of the defective hard tissue.
MCPM is highly water-soluble and is mostly used as a component in various injectable, self-hardening CaP cements. This phase is not naturally occurring in the body and its acidity makes it non-biocompatible; however, it has food grade and is also used as an additive in toothpaste and edible products.
DCPD and DCPA have relatively high resorbability rates that can conveniently be tuned to comply with the formation of new bone under physiological conditions.
DCPD is biocompatible, biodegradable and osteoconductive and depending on pH can also convert into other CaP phases such as DCPA, OCP or CDHA. It is used in craniomaxillofacial implants, as well as tooth fillers, anti-caries- and polishing agents.
α-TCP resorbs quickly, but it can also undergo hydrolysis to form CDHAp, which makes it useful in self-hardening formulations.
CDHAp and HAp are the phases that more closely resemble biological apatite. Moreover, HAp is the most stable and least soluble of all CaP phases and because it is bioactive and osteoconductive, it is used as a bone graft material when resorption is not necessary. Its applications vary from atrophic alveolar ridge augmentation, reparation of long bone defects, middle ear prosthesis, spinal fusion devices, injectable materials for vertebroplasty to craniomaxillofacial implants. β-TCP is widely used in orthopedics and dentistry as a resorbable bone void fillers in the form of porous granules or blocks. As opposed to poorly degradable HAp, β-TCP resorbs and can slowly be replaced by bone.
Metastable phases such as OCP and TTCP slowly hydrolyse into HAp when implanted in aqueous environments such as the human body. OCP is structurally very similar to HAp and it has been suggested to be one of the precursors of human bone. It is used as an implantable bulk material in bone defects, or in biocoatings and self-hardening formulations. TTCP is the most alkaline of all CaPs and therefore its antimicrobial properties have been exploited.
ACP is poorly crystalline, and has the ability to release ions which gives it the capacity to regulate the pH or to stimulate bone formation in aqueous environments; therefore, it is widely used in oral products which require an added delivery effect; that is, toothpastes, bleaching gels, and mouth washes.
These man-made bone replacements are more common than one might think and there is a variety of commercial products consisting of one or more of these materials, that are currently available in the market, for example: α-BSM®, Biopex®, Bone source®, Calcibon®, Cementek®, ChronOS inject®, Mimix®, Norian-SRS , Adbone®TCP, and Cerament®.
The semi-artificial skull: Sci-fi or transhumanist reality?
As early as 1065-740 BC, wooden prosthetics were already used to replace amputated body parts in ancient Egypt . More than 3000 years later, the use of artificial bone implants is becoming common ground in our increasingly advanced society, much to the anticipation of the transhumanist movement whose vision of civilisation is that of posthumans using technology and reason to overcome our intellectual and physical limitations.
The human skull is probably one of the most important sets of bones since it houses our brain and most of our sensorial organs. Therefore cranioplasty has important implications for protective, sensorial, and aesthetic aspects. According to some market research reports , the global craniomaxillofacial implant market is expected to reach over 3000 Million USD by 2025. This in turn will result in more options available to patients and craniofacial products becoming more accessible to the general public.
This technological uprising resulting from people generally becoming wealthier and healthier, has stimulated biomaterials development and brought about novel material-based cranioplasty solutions such as OssDsign®Cranial patient-specific implant by the Swedish company OssDsign AB.
This innovative product consisting of a 3D-printed titanium frame embedded in a mosaic tile layer consisting of mostly DCPA is an example of the current state-of-the-art expertise bringing together materials science, CAD, 3D-printing, and cranioplasty. The implant is not only able to regenerate bone and blood vessels around it but it leads towards less postoperative complications than the patients’ own biological bone .
Arguably, and depending on the translator’s interpretation, Aristotle tried to point out the idea that «the whole is greater than the sum of its parts» (Aristotle, Metaphysics 8.1045a). In our current context, this concept appears sharply applicable to the development of implantable materials and devices.
The sweet spot in the materials science paradigm that describes the relationship between structure, process, and properties has been found, causing modern synthetic calcium phosphates being, in some cases, better than bone and making the lines between reality and sci-fi most certainly blurred.
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