**1. Introduction**

Calcium phosphate is the group name of minerals consisting of diverse ions. The fundamen‐ tal ion group calcium (Ca2 + )is coupled by the orthophosphates—a basic ion of distinctive atoms andmoleculeswithinvaryingorganisms toformmanydifferent compoundsessentialtovitality [1]. Metaphosphates and pyrophosphates and occasionally hydroxide or hydrogen ions also contribute this family forming various combinations of crystalline configurations [2]. Mineral‐ ization of these ions and molecules constitutes the main frame of multicellular residents (the bone) including the human [3]. Some of the important subcategories of the calcium phos‐ phates are as follows:

#### **1.1. Mono calcium phosphate**

Monocalcium phosphate is an inorganic compound mainly found as monohydrate salts. Monocalcium phosphates are widely used in the food industry to enhance baking, rising, and longevity issues. One of the main ingredients in baking powder is monocalcium phosphate. It is also used as a leavening agent in various processes. Phosphoric acid is used to treat the monocalcium phosphates to sustain their purity. Together with the fluorapatite, it can be converted to superphosphates, which are used in fertilizers [3].

#### **1.2. Di-calcium phosphates**

This form of the calcium phosphates mainly consists of the "brushite"-type calculus and could be formulated as monohydrate dihydrate and anhydrous crystalline structures. They are used as a dietary supplement in many of the low-calorie foods [4].

#### **1.3. Tri-calcium phosphates**

The calcium phosphate of phosphoric acid is named as tri-calcium phosphate and mainly derived from inorganic substances such as whitlockite mineral rocks. Tri-calcium phosphates are one of the main metabolic products of bone tissue and—the beta tri-calcium phosphates especially have been under serious investigation by many researchers. With the evolution of sophisticated techniques and controlled sinterization methods, a biphasic form was supplied and termed as "biphasic calcium phosphate." This final form provided significant benefit, especially in bone surgery. A powder and liquid form which could be provided in a small physical carrier could be mixed and injected to the desired area like a tool paste. The material can be shaped and contoured *in situ,* and a hardening process takes place within 10 min. This is of utmost importance in bone defects requiring space maintenance. A semi-permeable membrane could be played over the hardened biphasic calcium phosphate body for further osteogenesis [5].

#### **1.4. The calcium apatite**

It forms the hydroxyapatite by a hexagonal crystalline system which 70% of the body bone mass is made of. Accordingly, hydroxyapatite can be considered as a principal component of the human skeleton, including the teeth dentin and enamel. The carbonated calcium-deficient hydroxylapatite which is a modified form of the hydroxyapatite is the foremost mineral in teeth tissues. Regarding the importance of the material, many synthesis methods were proposed including wet chemical deposition, sol–gel route (wet-chemical precipitation), electrodeposition, and biomimetic deposition. Hence, many studies yielded an enhanced response of the bone tissues when the hydroxyapatite is implanted. Consequently, many modern joints or hip prostheses are coated by hydroxyapatite to facilitate healing and os‐ seointegration (direct bone deposition on the titanium surface). This approach was also used in the dental implants, but higher production costs and relatively lower bone-contact surface of dental implants did not justify its feasible use. Blocks of porous hydroxyapatite are also used for the restoration of the bone defects and local drug delivery [4].

Besides the mentioned types of calcium phosphates, there are other crystalline configurations such as octacalcium phosphate, tetracalcium phosphate, and amorphous calcium phosphate [6].

#### **1.5. CaP cement**

**1. Introduction**

172 Dental Implantology and Biomaterial

tal ion group calcium (Ca2

phates are as follows:

**1.1. Mono calcium phosphate**

**1.2. Di-calcium phosphates**

**1.3. Tri-calcium phosphates**

osteogenesis [5].

**1.4. The calcium apatite**

+

converted to superphosphates, which are used in fertilizers [3].

as a dietary supplement in many of the low-calorie foods [4].

Calcium phosphate is the group name of minerals consisting of diverse ions. The fundamen‐

andmoleculeswithinvaryingorganisms toformmanydifferent compoundsessentialtovitality [1]. Metaphosphates and pyrophosphates and occasionally hydroxide or hydrogen ions also contribute this family forming various combinations of crystalline configurations [2]. Mineral‐ ization of these ions and molecules constitutes the main frame of multicellular residents (the bone) including the human [3]. Some of the important subcategories of the calcium phos‐

Monocalcium phosphate is an inorganic compound mainly found as monohydrate salts. Monocalcium phosphates are widely used in the food industry to enhance baking, rising, and longevity issues. One of the main ingredients in baking powder is monocalcium phosphate. It is also used as a leavening agent in various processes. Phosphoric acid is used to treat the monocalcium phosphates to sustain their purity. Together with the fluorapatite, it can be

This form of the calcium phosphates mainly consists of the "brushite"-type calculus and could be formulated as monohydrate dihydrate and anhydrous crystalline structures. They are used

The calcium phosphate of phosphoric acid is named as tri-calcium phosphate and mainly derived from inorganic substances such as whitlockite mineral rocks. Tri-calcium phosphates are one of the main metabolic products of bone tissue and—the beta tri-calcium phosphates especially have been under serious investigation by many researchers. With the evolution of sophisticated techniques and controlled sinterization methods, a biphasic form was supplied and termed as "biphasic calcium phosphate." This final form provided significant benefit, especially in bone surgery. A powder and liquid form which could be provided in a small physical carrier could be mixed and injected to the desired area like a tool paste. The material can be shaped and contoured *in situ,* and a hardening process takes place within 10 min. This is of utmost importance in bone defects requiring space maintenance. A semi-permeable membrane could be played over the hardened biphasic calcium phosphate body for further

It forms the hydroxyapatite by a hexagonal crystalline system which 70% of the body bone mass is made of. Accordingly, hydroxyapatite can be considered as a principal component of

)is coupled by the orthophosphates—a basic ion of distinctive atoms

It is defined as a powder or a mixture of powders which following the mixing into water or an aqueous medium to a paste, reacting in room or normal body temperature by the formation of a precipitate containing of one or more calcium phosphate crystals and sets by the entan‐ glement of the crystals of that precipitate. In the hardening phase, the material can be injected into any desired area. This greatly improves the manipulation [7].

#### **1.6. Self-hardening injectable iCaP**

The self-setting forms of CaP were introduced by Brown and Chow [8]. The material gained high popularity and interest due to its mechanical and biologic properties [8]. When used as a grafting material, its application promoted a higher level of bone repairing with some noted problematic issues. The difference of the crystalline composition and final amorphous form was found to be not favorable in terms of biocompatibility [9]. This was overcome by different sintering and preparation techniques leaving a higher percentage of organic form in the latest setting.

In almost all clinical and experimental studies, the material was accepted and healed rapidly [3]. However, histologic sections revealed limited biodegradation of the material. This was especially critical when a functional implant is to be placed on the area. Any load-bearing functional implant is expected to be surrounded by living bone tissue, which is called as osseointegration [10]. Upon the use of alloplastic materials around load-bearing implants, the replacement of the grafting material was not of a concern. The inert behavior of the materials was favored rather than the bone replacement (creeping substitution). The widespread use of dental implants then yielded the need of bone replacement of any graft material applied for the treatment of the lost bone volume. Up until then, the term "resorption" was being used to define the dissolution of the grafting materials. However, this was rather associated with a pathologic response so "biodegradation" was used instead of resorption [11].

#### **1.7. Biodegradation**

Occasionally defined as "resorption" can be defined as the dissolution of the graft material by the body biology [1]. Specifically, when used in bone defects, the CaP are expected to be removed by polymorph nucleated cells and simultaneously replaced by bone deposition by osteoblasts and other bone-inducing cells. In the description of this process, the "resorption" term was being used to define a group of inflammatory cells and subsequent tissue repair. In contrast to the repair process, biodegradation was then found appropriate for defining the dissolution of organic materials for a regeneration result [12]. Biodegradation is especially used in product packing when environmental issues are considered [7]. The biodegradation potential is distinct in different graft materials (**Table 1**).


**Table 1.** Biodegradation and osteogenesis potential in various types of bone grafts.

#### **1.8. The relevance of the biodegradation in oral reconstruction**

The skeleton constitutes the principal internal framework that allows the structural integrity of the organs. It also provides many biomechanics aspects of mobility [13]. More than 200 different types of bones create a critical support for many of the organs and elements. Among these, the face and jawbones that are embriogenetically derived from the pharyngeal arch to have unique features from rest of the body bone that is constructed via the endochondral ossification. The neural crest that the skull is originating attains its particular characteristics for specific purposes such as the protection of the brain tissue and formation of the first digestion component: the jaws and teeth. Any loss or damage in the jaws or teeth was one of the major health problems that the humanity faced upon the early ages. Due to its accessibility, the calcium phosphates-based materials were the first choice in the repair and restoration of jawbones [14]. Initial application of the raw material was not practical due to the powder form. Following particulate forms, improved the outcomes. However, they yielded difficulty in the contention of the defect area in the presence of bleeding [15]. Especially in the oral cavity, the conceded are may be subjected to forces and irritating factors resulting with the geometric violation of the graft area and a poor outcome (**Table 2**).


**Table 2.** Classification of CaP materials and their biodegradation characteristics.

#### **1.9. Injectable CaP in clinical dentistry**

**1.7. Biodegradation**

174 Dental Implantology and Biomaterial

Within the same species

Between the different species (allografts)

Transfer from non-vital/ synthetic sources (alloplasts)

✔: Poor; ✔✔: moderate; ✔✔✔: strong.

(autografts)

Occasionally defined as "resorption" can be defined as the dissolution of the graft material by the body biology [1]. Specifically, when used in bone defects, the CaP are expected to be removed by polymorph nucleated cells and simultaneously replaced by bone deposition by osteoblasts and other bone-inducing cells. In the description of this process, the "resorption" term was being used to define a group of inflammatory cells and subsequent tissue repair. In contrast to the repair process, biodegradation was then found appropriate for defining the dissolution of organic materials for a regeneration result [12]. Biodegradation is especially used in product packing when environmental issues are considered [7]. The biodegradation

Surface resorption

Inconsistent and/or incomplete

Incomplete

The skeleton constitutes the principal internal framework that allows the structural integrity of the organs. It also provides many biomechanics aspects of mobility [13]. More than 200 different types of bones create a critical support for many of the organs and elements. Among these, the face and jawbones that are embriogenetically derived from the pharyngeal arch to have unique features from rest of the body bone that is constructed via the endochondral ossification. The neural crest that the skull is originating attains its particular characteristics for specific purposes such as the protection of the brain tissue and formation of the first digestion component: the jaws and teeth. Any loss or damage in the jaws or teeth was one of the major health problems that the humanity faced upon the early ages. Due to its accessibility, the calcium phosphates-based materials were the first choice in the repair and restoration of jawbones [14]. Initial application of the raw material was not practical due to the powder form. Following particulate forms, improved the outcomes. However, they yielded difficulty in the

**(osteoconductivity)**

✔ ✔✔✔

✔✔ ✔

✔✔✔ Not applicable

**Vital cell proliferation (osteogenesis)**

potential is distinct in different graft materials (**Table 1**).

**Type of graft transfer Bone-inducing effect (osteoinductive) Space maintenance**

Potency ✔✔

Potency ✔

Potency ✔

**Table 1.** Biodegradation and osteogenesis potential in various types of bone grafts.

**1.8. The relevance of the biodegradation in oral reconstruction**

Biodegradation characteristic

Biodegradation characteristic

Biodegradation characteristics

Amorph and hydrous forms opened a new horizon with the cement-like setting feature. In this form, a powder (amorph component) and liquid (hydrous form) component is mixed to create a reaction of hardening just like a cement. While in its hardening stage, the material is in a "flowable" state allowing easy transfer and shaping according to the defect-site-specific conditions. This feature is then used as "inject ability" for enhancing the practical aspect of the calcium phosphate-based bone-grafting sequence. The primary results were favorable except one phenomenon present in almost all histologies. The core of the material was found intact *in situ* despite the abundant bone formation in the graft-to-host bone border. Initial observa‐ tions revealed that the material was highly biocompatible but lacked porosity yielding a bulky end product. As a result, the body fluids could penetrate the material only from the surface but did not reach to the core of the material. This aspect may of course be advantageous in some specialties of dentistry such as endodonty. The material applied to the root of the natural teeth after the removal of the vital structures known as the root canal therapy. The material successfully sealed the canals (even the side canals known as the *isthmus*) hermetically and caused no foreign material reaction the tooth-apex. The resistance of the material to resorption and biodegradation allowed long-term stability and success of the treatment known as the root canal therapy. However, in the restoration of the lost bone volume, the lack of complete translation of the injectable calcium-phosphate-bone cement (iCaP) into the bone tissue was a challenge [16]. Especially in oral implantology where a titanium fixture is expected being surrounded by living bone tissue (osseointegration) and any intact form of graft material was undesirable (**Figure 1**).

**Figure 1.** A dental implant placed into the alveolar crest should be surrounded by living bone tissue. Any lack of bone that is described as the dehiscence defects (intermittent lines) should be covered by a graft material with an osteogene‐ sis potential.

#### **1.10. Biodegradation of injectable CaP**

Many attempts have been undertaken to overcome the issues related to biodegradation of the iCaP. A series of powder and mixture settings was formulated and experimented on animal models to reveal the best configuration. The hydrous component allowed fine-tuning of the setting time and flowability characteristics, while the powder component was mainly related with the final hardness of the cement. Concomitantly, a porous character was obtained for gaining better flow and penetration by bodily cells and fluids. A delicate balance of the setting time, ease of injectability, and the final setting hardness was a constant challenge in the development stage in many previous studies [17].
