Biomaterials for Bone Regeneration

Novel Techniques and Applications

P. Dubruel, S. Van Vlierberghe

• Publisher: Woodhead Publishing
• Year: 2014
• ISBN:
  9780857098108
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

Novel Biomaterials for Bone Regeneration provides a comprehensive review of currently available biomaterials and how they can be applied in bone regeneration. In recent decades, there has been a shift from the idea of using biomaterials as passive substitutes for damaged bones towards the concept of biomaterials as aids for the regeneration of a host's own bone tissue. This has generated an important field of research and a range of technological developments.

Part one of this book discusses a wide range of materials, including calcium phosphate cements, hydrogels, biopolymers, synthetic polymers, and shape memory polymers. Part two then turns to the processing and surface modification of biomaterials, as well as how biomaterials can be evaluated both for their mechanical properties and for immunocompatibility with the host. Finally, part three covers a variety of cellular approaches, and production and delivery of biomaterials for bone regeneration. Chapters also consider the potential of electromagnetic and ultrasonic stimulation of biomaterials to aid in the regenerative process.

Novel Biomaterials for Bone Regeneration represents an important resource for academics, clinicians, and industry professionals working in the area of biomedical materials, providing them with both an overview of the current state-of-the-art, and an indication of potential future developments.

• Provides comprehensive coverage of novel materials, techniques, and applications of biomaterials for bone regeneration
• Provides vital information on the various types of materials used in bone regeneration
• Discusses processing, modification, and evaluation techniques of biomaterials, and looks at cellular approaches and stimulation of biomaterials for bone regeneration

Part I

Materials for bone regeneration

Outline

1 Calcium phosphate cements for bone regeneration

2 Injectable calcium phosphate cements for spinal bone repair

3 Hydrogels for bone regeneration

4 Combinations of biopolymers and synthetic polymers for bone regeneration

5 Applications of shape memory polymers (SMPs) in mechanobiology and bone repair

1

Calcium phosphate cements for bone regeneration

G. Cama, King’s College London, UK

Abstract:

This chapter reports an overview of calcium phosphate cements (CPCs) for bone tissue regeneration. The chapter first reviews the chemical formulations adopted to produce apatite, brushite and monetite cements together with the variables affecting the kinetics of the setting reactions. The chapter then discusses the overall material properties in terms of setting time, porosity and mechanical strength. The chapter includes the current clinical applications of the different CPCs and their unmet clinical needs.

Key words

calcium phosphates; bone cements; monetite; setting reactions; regenerative medicine

1.1 Introduction

The reconstruction of extensive bone defects remains a technical challenge and places a high clinical demand on synthetic substitutes that have osteoconductive and osteoinductive properties and possess adequate mechanical properties. Autologous bone grafting is currently considered the golden standard for restoring bone defects. The bone is generally harvested from the iliac crest, and this living bone contains osteogenic factors that can stimulate bone formation. However, clinical benefits can vary as the cellular components may be damaged during transplantation and there is the possibility of donor site morbidity. Complications can occur with autologous bone grafting: it is estimated that about 8–39% of cases show varying degrees of problems.¹ Calcium phosphates, ceramics and cements have been accepted for use in bone grafting and are currently the preferred synthetic substitutes due to their chemical similarity to the mineral component of bone. Ideally, a bone substitute should have mechanical properties similar to those of the host bone so that it allows cellular ingrowth, supports the formation of new bone and degrades over time as the new bone replaces the substitute. These are challenging requirements; a recent review by Stok et al.² and a comparative study of six bone graft substitutes by Seebach et al.³ reported that, despite the availability of numerous bone substitutes, there is little clinical evidence to support its use and there is a wide variation in the ways that a substitute supports cell survival and function. Calcium phosphates can be essentially divided into two categories: cements or ceramics. Hydroxyapatite (HA) derived grafts are ceramic in nature and are usually obtained through sintering at temperatures greater than 1000°C. α and β-tricalcium phosphate (α, β-TCP), sintered hydroxyapatite (SHA) and tetracalcium phosphate (TTCP) are other phases that can be obtained via sintering methods and are generally used in a granular form. CPCs, on the other hand, are considered an excellent synthetic material to fill bone cavities, defects or discontinuities.^{4, 5} This is because they are biocompatible and osteoconductive mouldable or injectable pastes that are able to self-set in a bone cavity,⁶ thereby avoiding the use of preformed materials that are designed to fit the surgical site around the implant and machine the graft to the cavity shape, which can lead to increase in bone loss.⁷ Moreover, drugs or cells previously encapsulated in a polymeric phase in order to prevent dead cells due to the mixing of the cement precursors may be incorporated into the cement paste, creating a cell-encapsulating scaffold with improved biological properties,⁸ and 3D printing of CPCs provides a promising new method for the fabrication of patient-specific implants.^{9, 10} The chemical reaction that forms the material is activated by mixing several calcium phosphate phases with a liquid phase. Depending on the pH of the chemical reaction, two types of cement can be obtained: when the pH ≥ 4.2, the reaction product is HA,¹¹ and when the pH < 4.2, the product is brushite (dicalcium phosphate dehydrate (DCPD))¹² or monetite (dicalcium phosphate anhydrous (DCPA)).¹³ Hydroxyapatite-based materials have a low resorption rate due to their poor solubility at a physiological pH level. In contrast, brushite and monetite have raised considerable interest in the last decade because they are metastable under physiological conditions and can be resorbed more quickly than stable HA cements.¹⁴ However, CPCs are brittle and can only be used in non-load bearing implants. Currently, studies related to the development of ‘ideal’ CPC are focused on the achievement of optimum balance between resorbability, porosity and mechanical properties. This chapter will provide an overview of CPCs and their application in regenerative medicine.

1.2 Calcium phosphate cements (CPCs)

Calcium orthophosphates can be used as reagent powders for the CPCs. These are calcium salts that are derived from orthophosphoric acid, which may be obtained by precipitation at room temperature or above. Calcium orthophosphates are made of calcium, phosphorous and oxygen. The hydrogen in the chemical composition of the compound can be found as an acid orthophosphate or as incorporated water, as in DCPD, also known as brushite (DCPD: CaHPO₄ · 2H₂O).⁴ The different calcium orthophosphate phases are generally distinguished by their calcium to phosphate molar ratio (Ca/P) and solubility. Table 1.1 shows a list of different calcium orthophosphate compounds. Among them, monocalcium phosphate monohydrate (MCPM), DCPA, DCPD, amorphous calcium phosphate (ACP), β, α-TCP and TTCP can be used as reactant powders for CPCs.

Table 1.1

Calcium orthophosphate compounds

Ca/P Molar ratio	Compound	Chemical formula
0.5	Monocalcium phosphate monohydrate	Ca(H2PO4)2 · H2O
1.00	Brushite (DCPD)	CaHPO4 · 2H2O
1.00	Monetite (DCPA)	CaHPO4
1.33	Octacalcium phosphate (OCP)	Ca8(HPO4)2(PO4)4 · 5H2O
1.20–2.20	Amorphous calcium phosphate (ACP)	CaxHy(PO4)z · nH2O, n = 3–4.5; 15–20% H2O
1.50	α-Tricalcium phosphate (α-TCP)	α-Ca3(PO4)2
1.50	β-Tricalcium phosphate (β-TCP)	β-Ca3(PO4)2
1.67	Hydroxyapatite (Hap)	Ca10(PO4)6(OH)2
1.67	Fluorapatite (FAP)	Ca10(PO4)6 F2
2.00	Tetracalcium phosphate	Ca4(PO4)2O

1.2.1 Metastable cements

The chemical reaction that forms CPCs can be activated by mixing the reagent quantities manually or mechanically. During this step, the calcium phosphate powder starts to dissolve in the liquid phase. Depending on the thermodynamic and kinetic factors, the precipitation process produces a crystalline calcium phosphate nucleus that grows until an interlocking crystal network is formed. The thermodynamic behaviour of several calcium phosphate compounds in the ternary system Ca(OH)₂-H₃PO₄-H₂O can be predicted by the singular points of the solubility isotherm diagram.¹⁵ HA is the more stable phase if the pH ≥ 4.2. On the other hand, DCPA is the more thermodynamically stable phase for lower pH values of the same singular point. However, the precipitation kinetic of monetite is lower than brushite, hence this latter phase is generally found as the main product of the hardening process. In the last decade, interest towards chemical phases with greater solubility than HA has increased. This interest is due to the ability of metastable phases (such as brushite and monetite) to be resorbed quickly by the implant site, which replaces them with the newly regenerated tissue.¹⁶

1.2.2 Apatite cements

In the early 1920s, a CPC was produced by hydrolysis of α-TCP and used for bone treatment for the first time.¹⁷ Since this date, different chemical formulations have been developed. Table 1.2 shows some of the commercially available apatite CPCs. By observing the thermodynamics of the ternary system Ca(OH)₂-H₃PO₄-H₂O, precipitated hydroxyapatite (PHA) or calcium deficient hydroxyapatite (CDHA) cements can be obtained by hydrolysing calcium phosphate (by mixing two calcium phosphates, one of which is TTCP) or by using a system formed by two calcium phosphate powders that have a Ca/P ratio lower than the stoichiometric ratio for HA (Ca/P = 1.67).¹⁸

Table 1.2

Chemical formulations of some apatite commercial CPCs

Manufacturer	Cement name	Chemical formulation	End product
Stryker-Leibinger Corporation	BoneSource®	Powder: TTCP (73%), DCP (27%) Solution: H2O, mixture of Na2HPO4 and NaH2PO4	Apatite
Biomet	Calcibons®	Powder: α-TCP (61%), DCP (26%), CaCO3 (10%), PHA (3%) Solution: H2O, Na2HPO4	Apatite
Kyphon	KyphOsTM®	Powder: α-TCP (77%), Mg3 (PO4)2 (14%), MgHPO4 (4.8%), SrCO3 (3.6%) Solution: H2O, (NH4)2HPO4 (3.5 M)	Apatite
Synthes-Norian	Norian SRS® Norian CRS®	Powder: α − TCP (85%), CaCO3 (12%), MCPM (3%) Solution: H2O, Na2HPO4	Apatite

The setting time of the chemical reaction that is involved in the formation of the PHA from the hydrolysis of one calc...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributor contact details
• Woodhead Publishing Series in Biomaterials
• Dedication
• Foreword
• Part I: Materials for bone regeneration
• Part II: Processing, surface modifi cation and evaluation of biomaterials for bone regeneration
• Part III: Cellular approaches and physical stimulation of biomaterials for bone regeneration applications
• Index