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Calcium phosphate
bone cement
By
Ahmed Mostafa Hussein
Assistant Lecturer, Department of Dental Biomaterials,
Faculty of D...
Calcium phosphate cement
Introduction
Types of bone grafts
Autografts: bone from the same individual (the gold
standard).
Allografts: another indiv...
Disadvantages of autografts
 Morbidity at the donor site.
 Limited availability of bone.
 Require a second surgery at t...
Disadvantages of allografts & xenografts
 Do not provide viable osteogenic cells
 Possible immune response.
 Disease tr...
Disadvantages of synthetic HA (stoichiometric &
crystalline)
 Brittleness
 Very slow resorbability. Long-term complicati...
Definitions
Osteoconduction means that bone grows on a surface.
Osteoconductive surface is one that permits bone
growth on...
Osteoinduction involves the stimulation of
osteoprogenitor cells to differentiate into osteoblasts
(bone-forming cells) th...
Osteointegration describes a process whereby clinically
asymptomatic rigid fixation of alloplastic materials is
achieved, ...
Table 1: Existing calcium phosphates (CaPO4) and their major properties.
Definition
Calcium phosphate cement (CPC) consists of one or
more calcium phosphate powders, which upon mixing
with water ...
Apatite-forming CPCs Brushite-forming CPCs
Hydrolysis of
α-TCP
Acid-base reaction
TTCP + DCPA/DCPD
Acid-base reaction
β-TC...
CPCs: Calcium phosphate cements
α-TCP: α-Tricalcium phosphate
TTCP: Tetracalcium phosphate
DCPA: Dicalcium phosphate anhyd...
Form
Powder & liquid
Composition
Powder
One or several calcium phosphate compounds.
Liquid
Distilled water or a calcium or...
Setting reaction
 Apatite-forming CPCs: acid-base reaction or
hydrolysis.
Examples
Hydrolysis of α-TCP.
Acid-base reactio...
After hardening, all formulations can form only two
main end-products:
Calcium-deficient hydroxyapatite (CDHA) at pH > 4.2...
Manipulation
Mixing
 Manual mixing: using a mortar and either a pestle or
a spatula.
Disadvantage: insufficient and inhom...
Calcium phosphate cements
Placement
Applied by the fingertips of a surgeon or
injected from a syringe.
Properties
 Besides having excellent biological behavior, being
injectable and self-setting in vivo at body
temperature a...
1. Setting time
Factors which could reduce the setting time
(i) Smaller particle size (high specific surface area)
(ii) Lo...
2. Cohesion and anti-washout ability
 Cohesion is the ability of a paste to keep its
geometrical integrity in an aqueous ...
 Another definition of cohesion is the ability of a CPC
to harden in a static aqueous environment without
disintegrating ...
 Numerous biopolymers, such as sodium alginate,
hydroxypropyl methylcellulose (HPMC), hyaluronic
acid, chitosan and modif...
The two best methods to increase the cohesion
(i) Smaller particle size
(ii) Increasing the viscosity
 However, they may ...
3. Injectability
 Injectability is defined as an ability of a formulation
to be extruded through a small hole of a long n...
Factors which could increase the injectability
(i) Increasing the L/P ratio
(ii) Decreasing the viscosity
(iii) Smaller pa...
4. Mechanical properties
4.1. Strength
 CPCs can be prepared with compressive strengths
comparable to those reported for human cancellous
bone (4-12 MPa) or cor...
 In similar conditions, dry samples have a higher
strength than wet samples.
 The smaller the particle size of the start...
 A general conclusion is obtained: crystalline
structures that are more compact and
homogeneous, with smaller crystals, s...
4.2. Fracture toughness
 Fracture toughness (KIc) is a property which is used
to describe the ability of a material conta...
 KIc values are comparable to the reported values for
cancellous bone (0.1-0.8 MPa.m1/2), but much lower
than those for c...
4.3. Reinforcement of CPC
 Carbon nanotubes (CNT) and multi-walled carbon
nanotubes, which find wide applications in sintered
HA–CNT composites, ha...
 Incorporation of 10 wt% CaCO3 causes a decrease in
crystallite size and improved compressive strength
by a maximum of 40...
 However, these additives generally have optimal
concentrations that can be used in the cement,
whereas a higher concentr...
Fiber-reinforced CPC
 The incorporation of fibers into brittle cement
improves fracture toughness as well as tensile and
flexural strength.
 ...
Fig. 2. Schematic illustration showing three mechanisms of fiber reinforcement
(fiber bridging, crack deflection and frict...
 Specifically, first, when the matrix starts to crack,
the fibers bridge the crack to resist its further
opening and prop...
* These two mechanisms have also been reported to be
the major contributors to the fracture toughness of
human bone, which...
 Due to the chemical similarity between CPCs and
cements for civil engineering, it is strongly expected
that, by adding f...
 A fiber with a high tensile strength is essential.
 Fiber length, volume fraction, orientation and
fiber/matrix adhesio...
 The mechanical properties gradually increased with
increasing fiber volume fraction.
 However, a plateau or a decrease ...
 A similar evolution in mechanical properties was
also found in CPCs with increasing fiber length. The
authors ascribed t...
Types of fibers
 Non-resorbable fibers: collagen fibers, polyamides,
carbon fibers and glass fibers.
 Resorbable fibers:...
 The incorporation of non-resorbable fibers into
resorbable CPCs could cause fiber release into the
surrounding tissues, ...
 To solve this problem, several types of fibers having
different resorption rates could be used
simultaneously. The fast ...
5. Bioresorption
 Brushite-forming CPCs are soluble in physiological
conditions, and therefore they degrade and resorb
in...
 At physiological pH, the in vitro solubility of DCPD is
approximately 100 times higher than that of β-TCP;
roughly, the ...
 Osteoclastic cells degrade the hardened calcium
phosphates layer-by-layer only (from outside to
inside) due to lack of m...
Bioresorption mechanism
 Active resorption: by the cellular activity of
macrophages, osteoclasts and other types of livin...
 Dissolution might be both chemical and physical.
 The former occurs with calcium phosphates of a low
solubility (those ...
 For example, for MCPM, MCPA, DCPD and DCPA the
solubility product are several times higher;
therefore, they might be phy...
 Osteoclastic cells resorb calcium phosphates with
Ca/P ratio > ~1.3 by providing a local acidic
environment which result...
Advantages
1) Self-setting ability in vivo.
2) Can be injected directly into the bone defects,
where they intimately adapt...
3)Minimal invasive surgery, quicker recovery & less
pain. Shorter hospital stays cheapen the expenses
(low cost).
4) Bioco...
6) Can be loaded with drugs (drug delivery system).
7) Easy manipulation.
Disadvantages
1. Brittleness and low fracture toughness limit their
application to non-stress bearing areas.
2. Lack of ma...
3. Can washout from surgical defect if excess of blood.
Compression during setting is recommended. In
addition, formulatio...
Applications
 Bone substitute &repair of bone defects in non-
stress bearing areas, e.g., craniofacial applications.
 Bo...
 Drug delivery system: for the treatment of bone
diseases, e.g., tumours, osteoporosis and
osteomyelitis, which normally ...
Recent advances
1. Two liquids or pastes
2. Automix
3. Premixed CPC
4. Fibers having different resorption rates
1. Two liquids or pastes
 An aqueous one and a non-aqueous one based on
glycerine.
 Advantage: easier to homogenize than...
2. Automix
 Twin-chambered syringe that allows injection
immediately after mixing.
Advantages
* More homogenous mix witho...
3. Premixed CPC (water-settable cement)
 Already prepared paste, which is stored until use.
 A non-aqueous but water-mis...
4. Fibers having different resorption rates
 The fast degradable fibers create pores for bone
ingrowth, while fibers with...
References
1. Zhang J, Liu W, Schnitzler V, Tancret F, Bouler JM. Calcium
phosphate cements for bone substitution: Chemist...
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Calcium phosphate bone cement presentation

  1. 1. Calcium phosphate bone cement By Ahmed Mostafa Hussein Assistant Lecturer, Department of Dental Biomaterials, Faculty of Dentistry, Mansoura University 2017
  2. 2. Calcium phosphate cement
  3. 3. Introduction Types of bone grafts Autografts: bone from the same individual (the gold standard). Allografts: another individual of the same species. Xenografts: bone from different species, usually bovine and coral origin. Alloplast: synthetic material.
  4. 4. Disadvantages of autografts  Morbidity at the donor site.  Limited availability of bone.  Require a second surgery at the donor site coupled with additional surgical risks, bleeding and possible infection.  Expensive procedure due to the prolonged hospital stay and extended medicare.
  5. 5. Disadvantages of allografts & xenografts  Do not provide viable osteogenic cells  Possible immune response.  Disease transmission.
  6. 6. Disadvantages of synthetic HA (stoichiometric & crystalline)  Brittleness  Very slow resorbability. Long-term complications include detachment of the coating from the implant and peri-implant infection, as HA is known not only as a bioactive mineral but also as an adsorbent. In other words, HA can adsorb bacteria.
  7. 7. Definitions Osteoconduction means that bone grows on a surface. Osteoconductive surface is one that permits bone growth on its surface or down into pores or channels. Osteoinductive material has the ability to induce bone formation by instructing its surrounding environment to form bone.
  8. 8. Osteoinduction involves the stimulation of osteoprogenitor cells to differentiate into osteoblasts (bone-forming cells) that then begin new bone formation.  Another proposed definition of osteoinduction is the process by which osteogenesis is induced. Osteogenesis is the process of new bone formation.
  9. 9. Osteointegration describes a process whereby clinically asymptomatic rigid fixation of alloplastic materials is achieved, and maintained, in bone during functional loading. (Albrektsson T, Johansson C. Osteoinduction, osteoconduction and osseointegration. Eur Spine J 2001; 10: S96–S101)
  10. 10. Table 1: Existing calcium phosphates (CaPO4) and their major properties.
  11. 11. Definition Calcium phosphate cement (CPC) consists of one or more calcium phosphate powders, which upon mixing with water or an aqueous solution form a paste that is able to set and harden forming either a non- stoichiometric calcium-deficient hydroxyapatite (CDHA) or brushite (dicalcium phosphate dihydrate, DCPD).
  12. 12. Apatite-forming CPCs Brushite-forming CPCs Hydrolysis of α-TCP Acid-base reaction TTCP + DCPA/DCPD Acid-base reaction β-TCP + MCPM/MCPA End-product: CDHA End-product: DCPD Better solubility under physiological conditions Faster reaction & setting Faster degradation & resorption in vivo Lower strength Most commercial products
  13. 13. CPCs: Calcium phosphate cements α-TCP: α-Tricalcium phosphate TTCP: Tetracalcium phosphate DCPA: Dicalcium phosphate anhydrous (monetite) DCPD: Dicalcium phosphate dihydrate (brushite) β-TCP: β-Tricalcium phosphate MCPM: Monocalcium phosphate monohydrate MCPA: Monocalcium phosphate anhydrous CDHA: Calcium-deficient hydroxyapatite
  14. 14. Form Powder & liquid Composition Powder One or several calcium phosphate compounds. Liquid Distilled water or a calcium or phosphate-containing solution.
  15. 15. Setting reaction  Apatite-forming CPCs: acid-base reaction or hydrolysis. Examples Hydrolysis of α-TCP. Acid-base reaction: TTCP + DCPA/DCPD.  Brushite-forming CPCs: acid-base reaction. Examples Acid-base reaction: β-TCP + MCPM/MCPA.
  16. 16. After hardening, all formulations can form only two main end-products: Calcium-deficient hydroxyapatite (CDHA) at pH > 4.2 or brushite (DCPD) at pH < 4.2.
  17. 17. Manipulation Mixing  Manual mixing: using a mortar and either a pestle or a spatula. Disadvantage: insufficient and inhomogeneous mixing thus compromises the strength.  Mechanical mixing: Better.
  18. 18. Calcium phosphate cements
  19. 19. Placement Applied by the fingertips of a surgeon or injected from a syringe.
  20. 20. Properties  Besides having excellent biological behavior, being injectable and self-setting in vivo at body temperature are the two main advantages of CPCs as bone substitutes.
  21. 21. 1. Setting time Factors which could reduce the setting time (i) Smaller particle size (high specific surface area) (ii) Low crystallinity (iii) Accelerators (iv) Higher setting temperature (v) Low liquid-to-powder ratio (L/P ratio).
  22. 22. 2. Cohesion and anti-washout ability  Cohesion is the ability of a paste to keep its geometrical integrity in an aqueous solution.  A bad cohesion may prevent setting and may lead to negative in vivo reactions due to the release of microparticles.
  23. 23.  Another definition of cohesion is the ability of a CPC to harden in a static aqueous environment without disintegrating into small particles.  The definition of the ‘‘anti-washout ability’’ is similar to that of cohesion, except that the former is evaluated in a dynamic aqueous environment.
  24. 24.  Numerous biopolymers, such as sodium alginate, hydroxypropyl methylcellulose (HPMC), hyaluronic acid, chitosan and modified starch, can significantly improve the cohesion and anti-washout of CPCs.
  25. 25. The two best methods to increase the cohesion (i) Smaller particle size (ii) Increasing the viscosity  However, they may in some cases compromise the setting time and mechanical properties.
  26. 26. 3. Injectability  Injectability is defined as an ability of a formulation to be extruded through a small hole of a long needle (e.g., 2 mm diameter and 10 cm length) Inj = (WF − WA)/(WF − WE) × 100% Inj is the percentage injectability WF is the weight of the full syringe WA is the weight of the syringe after the injection. WE is the weight of the empty syringe
  27. 27. Factors which could increase the injectability (i) Increasing the L/P ratio (ii) Decreasing the viscosity (iii) Smaller particle size (iv) Round particles
  28. 28. 4. Mechanical properties 4.1. Strength
  29. 29.  CPCs can be prepared with compressive strengths comparable to those reported for human cancellous bone (4-12 MPa) or cortical bone (130-180 MPa).  The strength decreases globally with increasing porosity.  With comparable porosities, apatite cements generally have higher strengths than brushite cements.
  30. 30.  In similar conditions, dry samples have a higher strength than wet samples.  The smaller the particle size of the starting materials, the faster they will convert into apatite and the smaller the apatite crystals formed, which, in turn, will lead to more and dense crystal entanglement and thus to an increase in strength.
  31. 31.  A general conclusion is obtained: crystalline structures that are more compact and homogeneous, with smaller crystals, seem to give better mechanical properties than less compact or less homogeneous ones with larger crystals.  It is difficult to increase strength of the self-setting CPCs without having a negative influence on the other properties.
  32. 32. 4.2. Fracture toughness  Fracture toughness (KIc) is a property which is used to describe the ability of a material containing cracks or notches to resist crack propagation.  CPCs have low fracture toughness (typically KIc < 0.5 MPa.m1/2).
  33. 33.  KIc values are comparable to the reported values for cancellous bone (0.1-0.8 MPa.m1/2), but much lower than those for cortical bone (2-12 MPa.m1/2), indicating that more effort is still required to increase the fracture toughness of CPCs for their application in load-bearing locations.
  34. 34. 4.3. Reinforcement of CPC
  35. 35.  Carbon nanotubes (CNT) and multi-walled carbon nanotubes, which find wide applications in sintered HA–CNT composites, have also been used as reinforcing agents in CPCs.  By adding certain amounts of apatite seeds, the setting time of CPCs decreased and the compressive strength concomitantly increased; conversely, however, excess apatite prolonged the setting time and decreased the compressive strength.
  36. 36.  Incorporation of 10 wt% CaCO3 causes a decrease in crystallite size and improved compressive strength by a maximum of 40% compared to samples free of CaCO3.  Hydroxyl acids (citric acid or glycolic acid) and their salts (sodium citrate), which allow easier mixing of the cement and processing with a decreased L/P ratio (relating to a decreased porosity), thus resulting in improved strength.
  37. 37.  However, these additives generally have optimal concentrations that can be used in the cement, whereas a higher concentration of such additives can decrease strength.
  38. 38. Fiber-reinforced CPC
  39. 39.  The incorporation of fibers into brittle cement improves fracture toughness as well as tensile and flexural strength.  In the fiber-added composite cements for civil engineering, three mechanisms of fiber reinforcement (fiber bridging, crack deflection and frictional sliding) appear to be operative (Fig. 2).
  40. 40. Fig. 2. Schematic illustration showing three mechanisms of fiber reinforcement (fiber bridging, crack deflection and frictional sliding) in fiber-added composite cements.
  41. 41.  Specifically, first, when the matrix starts to crack, the fibers bridge the crack to resist its further opening and propagation.  Secondly, crack deflection by the fibers prolongs the distance over which the crack propagates, consuming more energy in newly formed surfaces.
  42. 42. * These two mechanisms have also been reported to be the major contributors to the fracture toughness of human bone, which is a composite consisting of hard mineral nanoparticles (carbonated apatite) and a fibrous polymer (collagen). * Finally, the frictional sliding of fibers against the matrix during pullout further consumes the applied energy and increases the fracture resistance of the composite.
  43. 43.  Due to the chemical similarity between CPCs and cements for civil engineering, it is strongly expected that, by adding fibers, the above toughening mechanisms can also be achieved in CPCs.
  44. 44.  A fiber with a high tensile strength is essential.  Fiber length, volume fraction, orientation and fiber/matrix adhesion, are also critical for the final properties of the composite.
  45. 45.  The mechanical properties gradually increased with increasing fiber volume fraction.  However, a plateau or a decrease following the increase was often observed in the mechanical properties at high fiber volume.  This is mainly because the high volume of fibers may compromise their workability, making it difficult for them to be mixed and wetted by the CPC paste, leaving space between fibers and matrix.
  46. 46.  A similar evolution in mechanical properties was also found in CPCs with increasing fiber length. The authors ascribed the decrease in mechanical properties to the heterogeneous distribution of the long fibers.  The addition of chitosan lactate into the CPCs produced a stronger matrix to support the fibers to better resist crack propagation.
  47. 47. Types of fibers  Non-resorbable fibers: collagen fibers, polyamides, carbon fibers and glass fibers.  Resorbable fibers: natural or synthetic polyesters such as polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) or chitosan.
  48. 48.  The incorporation of non-resorbable fibers into resorbable CPCs could cause fiber release into the surrounding tissues, with the subsequent biocompatibility risks.  As for resorbable fibers, macropores produced from fiber degradation can promote bone ingrowth. However, these macropores are detrimental to the mechanical stability of CPCs before new bone grows into the pores.
  49. 49.  To solve this problem, several types of fibers having different resorption rates could be used simultaneously. The fast degradable fibers create pores for bone ingrowth, while fibers with a low degradation rate provide strength to the implant.
  50. 50. 5. Bioresorption  Brushite-forming CPCs are soluble in physiological conditions, and therefore they degrade and resorb in vivo faster than apatite-forming CPCs.  It might take from 3 to 36 months for different formulations to be completely resorbed and replaced by bone.
  51. 51.  At physiological pH, the in vitro solubility of DCPD is approximately 100 times higher than that of β-TCP; roughly, the same order of magnitude applies for the in vivo resorption kinetics of these calcium orthophosphates.  Porosity of self-setting calcium orthophosphate formulations is a very important factor for their biodegradability.
  52. 52.  Osteoclastic cells degrade the hardened calcium phosphates layer-by-layer only (from outside to inside) due to lack of macroporosity and interconnected pores.
  53. 53. Bioresorption mechanism  Active resorption: by the cellular activity of macrophages, osteoclasts and other types of living cells (phagocytosis).  Passive resorption: due to either dissolution or chemical hydrolysis (brushite-forming formulations only).
  54. 54.  Dissolution might be both chemical and physical.  The former occurs with calcium phosphates of a low solubility (those with Ca/P ratio > ~1.3).  The latter occurs with calcium phosphates of a high solubility (those with Ca/P ratio < ~1.3).
  55. 55.  For example, for MCPM, MCPA, DCPD and DCPA the solubility product are several times higher; therefore, they might be physically dissolved in vivo, which is not the case for α-TCP, β-TCP, CDHA, HA and TTCP.  Therefore, biodegradation of the latter materials is only possible by osteoclastic bone remodeling and is limited to surface degradation since cells cannot penetrate the microporous structure.
  56. 56.  Osteoclastic cells resorb calcium phosphates with Ca/P ratio > ~1.3 by providing a local acidic environment which results in chemical dissolution.
  57. 57. Advantages 1) Self-setting ability in vivo. 2) Can be injected directly into the bone defects, where they intimately adapt to the bone cavity regardless its shape (injectable, moldable & perfect adaptation).  Note: Being injectable and self-setting in vivo at body temperature are the two main advantages of CPCs as bone substitutes.
  58. 58. 3)Minimal invasive surgery, quicker recovery & less pain. Shorter hospital stays cheapen the expenses (low cost). 4) Biocompatible, bioactive & osteoconductive. 5) Bioresorbable & can be replaced by newly formed bone.
  59. 59. 6) Can be loaded with drugs (drug delivery system). 7) Easy manipulation.
  60. 60. Disadvantages 1. Brittleness and low fracture toughness limit their application to non-stress bearing areas. 2. Lack of macroporosity and interconnected pores, which prevents fast bone ingrowth, and the cements degrade layer-by-layer from the outside to the inside.
  61. 61. 3. Can washout from surgical defect if excess of blood. Compression during setting is recommended. In addition, formulations containing sodium alginate have been studied to solve this problem.  Unfortunately, the perfect grafting material does not exist. The self-setting CPCs are not an exception to this statement.
  62. 62. Applications  Bone substitute &repair of bone defects in non- stress bearing areas, e.g., craniofacial applications.  Bone filler for gaps around oral implants.  Bone augmentation.
  63. 63.  Drug delivery system: for the treatment of bone diseases, e.g., tumours, osteoporosis and osteomyelitis, which normally require long and painful therapies.  Other dental applications *Direct pulp capping: Compared to calcium hydroxide, both materials were equally capable of producing secondary dentin at ~24 weeks. *Pulpotomy.
  64. 64. Recent advances 1. Two liquids or pastes 2. Automix 3. Premixed CPC 4. Fibers having different resorption rates
  65. 65. 1. Two liquids or pastes  An aqueous one and a non-aqueous one based on glycerine.  Advantage: easier to homogenize than powder with liquid.
  66. 66. 2. Automix  Twin-chambered syringe that allows injection immediately after mixing. Advantages * More homogenous mix without air bubbles. * More reproducible. * Immediate injection into the bone defects. * Fast. * Less contamination risks.
  67. 67. 3. Premixed CPC (water-settable cement)  Already prepared paste, which is stored until use.  A non-aqueous but water-miscible liquid is used to prepare the paste.  Hardens after being injected into the bone defect.  Advantages: fast & no mixing.  Disadvantages: sensitive to moisture during storage & poor mechanical properties.
  68. 68. 4. Fibers having different resorption rates  The fast degradable fibers create pores for bone ingrowth, while fibers with a low degradation rate provide strength.
  69. 69. References 1. Zhang J, Liu W, Schnitzler V, Tancret F, Bouler JM. Calcium phosphate cements for bone substitution: Chemistry, handling and mechanical properties. Acta Biomaterialia 2014; 10: 1035–1049. 2. Dorozhkin SV. Self-setting calcium orthophosphate formulations. J Funct Biomater 2013; 4: 209–311. 3. Chow LC. Next generation calcium phosphate-based biomaterials. Dent Mater J 2009; 28: 1–10. 4. Ambard AJ, Mueninghoff L. Calcium phosphate cement: review of mechanical and biological properties. J Prosthodont 2006; 15: 321– 328.
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