Journal of Biomaterials Science, Polymer Edition

ISSN: 0920-5063 (Print) 1568-5624 (Online) Journal homepage: https://www.tandfonline.com/loi/tbsp20

Functionally Graded Biomimetic Biomaterials in

Dentistry: An Evidence-Based Update

Syed Saad Bin Qasim, Muhammad Sohail Zafar, Fayyez Hussain Niazi, Majid
Alshahwan, Hanan Abdel KS & Umer Daood

To cite this article: Syed Saad Bin Qasim, Muhammad Sohail Zafar, Fayyez Hussain Niazi, Majid
Alshahwan, Hanan Abdel KS & Umer Daood (2020): Functionally Graded Biomimetic Biomaterials
in Dentistry: An Evidence-Based Update, Journal of Biomaterials Science, Polymer Edition, DOI:
10.1080/09205063.2020.1744289

To link to this article: https://doi.org/10.1080/09205063.2020.1744289

Accepted author version posted online: 23

Mar 2020.

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Functionally Graded Biomimetic Biomaterials in Dentistry: An Evidence-Based Update

Syed Saad Bin Qasima,b,*, Muhammad Sohail Zafarc,d, Fayyez Hussain Niazie, Majid
Alshahwanf, Hanan Abdel KSg, Umer Daoodg

a
Faculty of Dentistry, Department of Biomaterials, University of Oslo, PO Box 1109,

Blindern, N-0317 Oslo, Norway Email. [email protected]

b
Department of Bioclinical Sciences, Faculty of Dentistry, Kuwait University, Kuwait.
c
Department of Restorative Dentistry, College of Dentistry, Taibah University, Medina

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Munawwarah, Saudi Arabia;

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d
Department of Dental Materials, Islamic International Dental College, Riphah International

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University, Islamabad 44000, Pakistan; [email protected]
e

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Department of Restorative and prosthetic dental sciences, College of dentistry, Dar al Uloom

University, Riyadh, Saudi Arabia. [email protected]

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f
Department of Rehabilitation Sciences, College of Applied Medical Sciences, King Saud
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University, Riyadh, Saudi Arabia. [email protected]

g
Clinical Dentistry, Restorative Division, Faculty of Dentistry, International Medical
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University Kuala Lumpur, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000 Bukit Jalil, Wilayah
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Persekutuan Kuala Lumpur, Malaysia, [email protected], [email protected]

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*Corresponding Author: Dr Saad B Qasim, Department of Biomaterials, Faculty of Dentistry,

University of Oslo, PO Box 1109, Blindern, N-0316 Oslo, Norway. Email:
[email protected]

Abstract
Design and development of novel therapeutic strategies to regenerate lost tissue structure and

function is a serious clinical hurdle for researchers. Traditionally much of the research is

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dedicated in optimizing properties of scaffolds. Current synthetic biomaterials remain

rudimentary in comparison to their natural counterparts. The ability to incorporate

biologically inspired elements into the design of synthetic materials has advanced with time.

Recent reports suggest that functionally graded material mimicking the natural tissue

morphology can have a more exaggerated response on the targeted tissue. The aim of this

review is to deliver an overview of the functionally graded concept with respect to

applications in clinical dentistry. A comprehensive understanding of spatiotemporal

arrangement in fields of restorative, prosthodontics, periodontics, orthodontics and oral

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surgery is presented. Different processing techniques have been adapted to achieve such

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gradients ranging from additive manufacturing (three dimensional printing/rapid prototyping)

to conventional techniques of freeze gelation, freeze drying, electrospinning and particulate

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leaching. The scope of employing additive manufacturing technique as a reliable and
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predictable tool for the design and accurate reproduction of biomimetic templates is vast by

any measure. Further research in the materials used and refinement of the synthesis
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techniques will continue to expand the frontiers of functionally graded membrane based
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biomaterials application in the clinical domain.

Keywords: Computational modelling, dentistry, functional gradients, finite element analysis,

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tissue regeneration, membranes

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1. Introduction
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Biomaterials research has focused extensively on conceptualizing, designing and fabricating

tissue engineered constructs with enhanced function. Although traditionally, much of the

research is dedicated to optimizing the properties of biomaterials by chemical modifications

of natural and synthetic composite formulations, recent reports [1–3] suggest the potential of

spatial and temporal control of existing materials so as to harness unique characteristics and

thereby, mimic the dynamics of nature or micro-environments in host tissues [4]. Devising

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novel therapeutic strategies for reconstruction and regeneration of orofacial tissues remains

the major clinical hurdles. A lesson that nature has taught mankind is its gradient approach.

In order to avoid stress concentrations and damage to tissues, nature has often employed

physical gradients at interfaces between tissues with varying biophysical and mechanical

properties. In order to hone the discipline of tissue engineering for devising bespoke

biomimetic templates, harnessing the triad of three major elements is key; namely the

membranes (scaffolds), pluripotent cell component or stem cells, and cell specific signaling

molecules which may also be present in the guise of growth factor (Figure. 1A)[5]. We have

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critically reviewed the available literature targeted on adapting a functionally graded approch

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focussed for craniofacial soft and hard tissues including periodontal tissue engineering

scaffolds, dental implants, and prosthetic restorations.

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The term “functionally graded materials” (FGM) was described as a class of
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engineering materials displaying spatially inhomogeneous microstructures and properties [6].

FGM are composite materials with variations in both chemical and structural characteristics
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aiming to achieve enhanced functionality and a variety of properties compared to

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homogenous materials. In addition, FGM exhibits a smooth transition between two different

materials to improve the long-term performance of the material. Two types of graded
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microstructures can be identified:

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(i) Layered microstructure (graded) where the properties of the material change in a

step-wise manner between different layers of the material

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(ii) (ii) Continuously graded microstructure where the property changes are gradual and

continuous through the material (Figure. 1B) [7].

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 Characterization of FGM materials can be undertaken via assessing certain

parameters that may range from denoting subtle variations in crystallinity, composition to

grain morphology. This would contribute significantly towards paving the way for delivering

customised functionalities at the cellular and sub cellular level [8]. A remarkable feature on

display at the enamel-dentin interface is the near seamless transition in hardness and

associated mechanical properties across a span of just 10 µm. This transition usually involves

an intermediate layer, where a gradual compositional change comprising elements from both

contributing tissue types (including a spectrum of extracellular matrix derived cytoskeletal

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components such as fibrous proteins and polysaccharides) are discernible at the micro and

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nanoscale [9].

Currently, the synthetic biomaterials remain at the rudimentary stage compared to

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their natural counterparts. The ability to incorporate biologically inspired elements into the
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design of synthetic material will advance with time as our understanding of functionality in

scaffolds and templates grow with time [10]. A structured search was conducted on
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PUBMED to investigate the studies being conducted on the concept of adapting functional
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gradients for dental implants and scaffolds/templates for periodontal regeneration.

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The last decade has borne witness to the exponential growth of tissue engineering and

allied disciplines in the realm of bioengineering in general and dental biomaterial

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development in particular. This can be attributed largely to a consistent and on-going

evolution process of the myriad of innovate techniques and the concurrent availability of

more sophisticated materials in the race to deliver novel bioactive and smart delivery systems

to the clinic [11]. However, the greater purpose of research is to understand nature and

translate it into different biomedical clinical applications. The concept of functional tissue

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engineering revolves around the perusal of the atomic and sub atomic elemental components

that constitute native tissues as a starting point. Working upwards, a hierarchical relationship

is sought that would aim to elucidate the intricate relationships deemed essential for coaxing

maximal function out of optimal structure – a critical threshold that requires surmounting if

an encompassing scaffold fabrication protocol is to be effectively devised. Such feats are

only possible through a rigorous exploitation of intricate characterization based analytical

techniques. The interface is a consistently occurring feature in nature and therefore beckons

due consideration when considering the reproduction of any aspect of interfacial tissue

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engineering. A standard go to technique for nature in this instance is stratification. Each layer

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that defines a stratified template model, details varying chemical and physical properties that

will contribute to the overall performance of the construct in vitro and in vivo (Figure 2).

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Such concepts have already been adopted in the tissue engineering of interfaces by a number
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of researchers [1,10–15].
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Among the examples available in nature for FG biomaterials, tooth structure has a unique
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hierarchical microarchitecture that is meant to deliver extra ordinary biomechanical

properties needed during masticatory process. In between the enamel and dentine interface is
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a functionally graded junction (dentine enamel junction) that allows the smooth transition of
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biomechanical properties [17,18]. Hardness is reduced from the outside enamel region

towards the dentine, whilst the toughness increases. Such an interface exhibits crack
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propagation from the enamel towards the dentine hence supporting the tooth integrity during

masticatory process[19].

2. Processing techniques for FGM

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A number of researchers have investigated the processing techniques for fabricating

functionally graded biomaterials [20–23]. The development of novel and innovative

manufacturing methods that can tightly harness the gradient of properties cost effectively

remains a challenge [24]. Some of the conventional techniques such as porogens,

impregnating cellulosic sponges into slurries of hydroxyapatite, centrifugation methods and

self-foaming followed by pyrolysis play a pivotal role in fabrication of templates [25]. Liu

and co-workers extensively reviewed the heterogeneities in biological materials and

highlighted on the design principles, functions as well as bioinspired applications utilizing

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functional gradients. There are two principle methods that to fabricate such gradients; [23]

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(i) Constructive processing, which refers to selective stacking of starting components in a

specific sequence such as vapour deposition and solid state powder metallurgy

(ii)
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(ii) Transport based processing, which utilizes transport based phenomenon such as heat
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and mass diffusion to create chemical and structural/functional gradients in materials.

Despite their widespread use in engineering design, these methods suffer from some
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shortcomings in terms of feasibility to accurately control the hierarchical local properties

in the manner achieved in biomaterials [26]. Recent advancements in nanotechnology has

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enabled an increasing control on biomaterial ultrastructures and properties.

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A porous biomaterial construct with a variable spatial porosity index has also been

proposed of late. Guided by customised algorithms entrenched in the principles of

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mechanobiology, the construct displayed a porosity distribution defined by a specific gradient

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(Figure 1). This can indeed be applauded as a venture on the road less travelled, since the

dearth of literature and work done on defining and subsequently characterising functional

gradient constructs have, for the most part, relied on conventional 3D printing and CAD-

CAM techniques for fabrication of such scaffolds [16,20–23].

Mi Soon and co-workers designed hydroxyapatite scaffolds with a unique twist. In

that their porous scaffolds boasted a core and shell design that was functionally graded

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through the freeze casting technique. The hydroxyapatite and camphene slurries with variable

hydroxyapatite content ranging from 20 to 36% volume were cast into fugitive mould

templates, with 3 dimensionally interconnected pores for obtaining a highly porous template

The slurries once casted were freeze-dried and sintered at 1250°C for 3 hours. Preliminary in

vitro osteoblastic activity indicated good biocompatibility [24]. Powder metallurgy has been

also investigated by Chenglin and co-workers to synthesize functionally graded

hydroxyapatite titanium biomaterials. Their findings conclusively singled out a design

derived from thermal stress relaxation for the manufacture of HA – titanium FGMs with

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optimised graded compositions [27,28].

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Since the fabrication and development of open porous templates have been hindered

by the limitations of different production techniques, there is an increasing demand for

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manufacturing procedures which can harness the porosity, pore size, distribution and
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biomechanical properties [29]. Taking on the challenge of designing synthetic materials with

advanced levels of regulation of the porosity index and composition, will yield synthetic
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structures that can be synthesised utilising infinite combinations of heterogeneities and

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gradients at variable scale lengths. This makes the process of mimicking biologically inspired

materials a reality [26]. Additive manufacturing can be harnessed for developing structures
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with multi-tiered architectural forms in a “bottom up” manner which could also overcome the
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issues of controlling properties [30]. The technique is also known as solid free form

fabrication (SFF), layered manufacturing or even direct digital manufacturing (DDM).

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Particularly the additive manufacturing is a combination of techniques that are able to

generate physical objects directly with considerable precision in morphology by harnessing

data mined from computer aided design (CAD) platforms [29].

A wide range of bio-manufacturing technologies have been described in the literature.

[31–33][30] A number of different materials such as polymers, metals and ceramics can be

7
effectively utilised in this way for fabricating templates imbued with a level of complexity

that can be detailed and specified at both sub-micron and macrometer levels. Nevertheless,

these reproductions suffer from their fair share of shortcomings; the most glaring one being

less than ideal reproduction of surface detail and texturing down to the nanoscale [34,35].

Hence, biomechanical properties related to properties such as fracture toughness, for

instance, are usually inferior to materials synthesised via conventional means [26].

The additive manufacturing and 3D printing are promising techniques for the next

generation of biomedical implants [30,31,36]. Mangano et al., conducted an extensive review

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of the current literature on direct metal laser sintering titanium dental implant [37]. Few

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clinical studies report on this technology for fabrication of dental implants [29]. Silva and co-

workers analysed the ability of selective laser sinters and 3D printing models to be able to

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reproduce maxillo-facial anatomy and their dimensional error (Figure 3). Tomographic
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images of a dry skull were manipulated and prototypes were prepared using selective laser

sinter and 3D printing. The results demonstrated higher dimensional precision and accurate
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reproducibility of craniomaxillary anatomy with the selective laser sintering approach

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compared to 3D printing [38]. Another technique that has also been reported to fabricate

bioinspired composites is magnetically assisted slipcasting. The process entails the deposition
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of a fluid suspension of particles into a dry porous mould of a pre-defined geometry and pore
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dimensions [39]. Wetting of the porous features generates capillary forces that continuously

extract the liquid phase from the suspension of fabricate a layers of cramped particles next to
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the mould wall. Sometimes reffered as the cake layer. Apart from capillary forces vacuum

can also be used to extract the liquid phase through the walls of the porous mould. Le Ferrand

et al have reported an extensive investigation conducted on using magnetically assisted slip

casting [39]. They demonstrated that it is a fast and powerful additive manufacturing route

for the fabrication of heterogeneous synthetic composites that is aimed to match the

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functional demands of specific target applications. The possibilities that it can target to make

complex shaped composites in highly mineralized systems significantly expands the design

space thus far available for making biologically inspired materials.

Mandibular reconstruction using stereolithography was investigated by Cohen et al.

[40]. The study looked into designing models for the preparation of bridging plates prior to

performing resection of a mandibular ameloblastoma. The study concluded that 3D printing

technology, in this instance, serves as a reproducible, accurate, efficient and cost efffective

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method of mandibular defect rehabilitation in the guise of a convenient surgical procedure

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[40]. The concept of FGM has been employed by investigators in a number of studies. Table

2 summarizes the studies conducted on modelling FGM and actual application of FGM

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concept to fabricate scaffolds or templates for the tissue engineering of lost craniofacial
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tissues and constructing prosthesis. Figure 4 shows the graded approaches that can be adapted

in dentistry.
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3. Functional gradients in orthodontic arch wires

Orthodontic arch wires have now been incorporated with graded functionality. These are
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categorized as superelastic nickel titanium ( Ni-Ti) orthodontic archwires. These wires are
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known to undergo transformation under ambient temperatures[58]. An investigation

conducted by Fernandes et al., reported that the load developed by these wires depends on the
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geometrical characteristics, the temperature and the strain. Conventional wires are able to

generate constant forces whilst undergoing a wide range of displacement during the

orthodontic treatment. A number of different synthesis techniques have been suggested in

order to overcome the different forces of actuation in the incisal and molar region. Laser

welding different wire segments or separate heat treatments of different parts in special

9
furnaces. Fernandes and co-workers used Joule heat effect to acquire a localized heath

treatment in order to get functionally graded superelastic NiTi orthodontic arch wires.

Differential scanning calorimetry measurements showed that a microstructural gradient was

present in such wires [58].

4. Graded approach for in prosthodontics

Graded dental restorations have shown to display improved features such as higher

resistance to sliding and contact[59], better and stronger adhesion of porcelain to the

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substructures [60], improve aesthetics and better behaviour under fatigue conditions

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compared to conventional restorations [61][57]. In addition, one dental application where an

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“ideal material” is yet to be fabricated is the root canal post. Currently, posts are fabricated of

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either flexible or rigid materials. Although flexible materials are highly recommended due to

their reported advantages such as reduced risk of root fracture, Young’s modulus similar to
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dentin, there are certain shortcomings. For instance, stress concentrations at the post-dentin
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interface ultimately leads to de-bonding of the post and movement of the core, eventually

causing microleakage and failure [55].

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FGM is a useful technique to fabricate all-ceramic restorations through glass

infiltration technology. It is a combination of a glass veneer with aesthetics, a reduced

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modulus and hardness with a ceramic core of higher strength, whilst avoiding a sharp contact
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at the interface. [62] The lack of an interface serves to revamp the bond strength by a
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considerable degree at the interfacial aspect, while simultaneously lowering chances of

delamination. The synthesis protocols of these templates are therefore quite straight forward

and more importantly, transferable to CAD/CAM technology with relative ease [63]. Zhang

and Kim have reported the use of glass infiltration method to make glass zirconia structures

that have a gradual change in the material’s elastic modulus. Zirconia templates with

somewhat low heat treatments are used for merging techniques involving the infiltration of

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glass and the densification process of zirconia. Using this approach, the glass infiltration

depth can be harnessed by altering the porosity of the zirconia templates [63].

Laser lithography was adapted by Matsuo et al., to fabricate a dental composite resin

based post. Laser lithography technology is one of the computer aided design

(CAD)/computer aided manufacturing (CAM) system adapted for fabricating solid models.

The technique is based on a photochemical reaction between a laser beam and light curing

system. The application of this technology in dentistry is still very limited and only a few

attempts have been performed to fabricate dental prosthesis. The graded structure achieved

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by Matsuo and co-workers showed gradual change in elasticity of the post. Moreover, finite

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element modelling analysis demonstrated the effect of stress relaxation at the apex of the post

and core, which could significantly contribute to reduction in root fractures during stress

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relaxations [55]. A similar study was also conducted by Watari et al. to fabricate a dental post
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using composite resins and laser lithography. The elastic modulus showed a gradual change

from 10.6 GPa in the core part to 2.9 GPa at the apex of the post by decreasing the filler
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content of the ceramic powders from 64% to 0% in the polymer matrix. Furthermore, finite
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element stress analysis showed the stress relaxation by 30% in the FGM material compared

to the uniform composite resin [48].

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Although bilayered systems were introduced for veneering application they had some
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biomechanical limitation with respect to fracturing [64]. These were mimicking functionally

graded interface strategies for prosthetic restorations. More recently multi-layered ceramic
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restorations fabricated with computer aided design and manufacturing have reported higher

fracture strength values when compared with crowns made of layering and press on technique

[65,66]. A drawback encountered by the use of multi-layered is that they are more prone to

chipping and delamination instead[66].

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5. Functional gradients for dental implants

In recent years, dental implants have been developed as one of the most successful treatment

options for the rehabilitation of space(s) left behind in the event of lost dentition. The on-

going evolutionary process of dental implant therapy as a whole is aptly on display in terms

of availability of increasingly sophisticated materials and innovative surgical options. This

evidently is exemplified in the clinical successes achieved thus far in a plethora of cases

requiring extensive and radical rehabilitative solutions. The current survival rate of oral

implants spanning a period of over a decade falls in between 80 and 95%.[67][51] Strength,

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durability and life span of an implant system is critically influenced by stress and its

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distribution [52]. The development and evolution of bioactive materials to enhance bone

bonding around the implant surface is a significant development in this context.

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Hydroxyapatite (HA) has always been regarded as an excellent compositional substitute for
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human skeletal and dental tissues [68]. HA coating on implant surface has been proven to be

osteoconductive, thereby reducing the osseointegration time. However, issues pertaining to

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rapid solubility and disintegration of pure HA based coatings are a standing issue responsible
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for implant therapy failure in such cases. To overcome this issue, fluoroapatites (FHA, Ca5

(PO4)3 (OH)1-x Fx) were developed. Fluoroapatites are able to enhance the deposition of
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calcium and phosphorus and by controlling the quantities of F- incorporation, it is possible to

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reach an equilibrium between short term bioactivity and long term stability [69].

Dental implant surface coating systems represent an example of FGM, wherein, the
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rationale behind such a coating is to avoid the mismatch between mechanical properties of

implant materials and biological properties of human bone tissues with subsequently

improved biocompatibility and stress distribution [61-62]. These graded structures have

received significant attention and could potentially pave the way for the arrival of a new

breed of dental implant products to the clinic. Axially graded configurations with a tapering

12
elastic modulus index in sync with the profile of the implant prosthesis from the cervical to

apical region, is one of the avenues open for exploitation and further refinement with respect

to the application of the FGM concept in the area of innovations in dental implant prosthesis

development [72]. Axial grading configurations tested using finite element analysis, show a

considerable reduction of stresses in the peri-implant bone interface coupled with enhanced

biocompatibility [46]. The required properties of functionally graded materials are presented

in Figure. 5, where A shows FGM implant and B shows a conventional uniform implant. In

case of the conventional implant, the strength and biocompatibility are constant across the

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implant surface while the FGM implant properties are variable based on the required need for

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each part of the implant [47].

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Finite element analysis have been conducted to test the possibility of developing a radial,
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functionally graded biomaterial to reduce the stress and offer a stress shielding effect around

the dental implant - bone interface. A high risk of crack formation at the dental implant-
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coating interface could be attributed to the wide utilization of HA in the recent decade

[51,52]. These cracks could be designated to sudden changes in the mechanical properties at
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the interface and iatrogenic deficiencies that occur during the manufacturing process. The
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material properties of the proposed implants started with a titanium core and terminates at a
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biocompatible ceramic (HA) at the outer layer that is in contact with the bone tissue.

Moreover, the optimal design of functionally graded biomaterial implant reduces the stress
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concentration in both cortical and cancellous bone compared to conventional titanium

implants. This reduction could lead to faster bone regeneration and early stabilization of the

implant [52]. Another study on design optimization of radial functionally graded dental

implants has reported. It would seem that implants bearing a coating that complied with a

reduced modulus rating exerted significantly reduced levels of maximum stresses at the peri-

implant bone interface without having a significant bearing on the average stresses generated

13
within the bulk of the prosthesis. Thereby contributing to a biomechanically favourable

environment. In instances where optimal thickness of coatings do not exceed 100µ such as a

zirconia – HA composite; a transitional modulus gradient is not deemed necessary to

implement [51]. Baino and Verné have also reported about the fabrication and

characterization of glass derived bilayered implant. The biomaterials was devised to have

bioactive bottom layer for bone bonding and aesthetic top layer integrated into the implant

system. The results suggested that multicomponent silicate glasses and their glass ceramic

derivatives could be used for whole tooth replacement [73].

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6. Periodontal tissue engineering utilizing the concept of functional gradients

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Successful regeneration of both mineralised and soft tissues for the sake of achieving

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complete restoration of critical sized craniofacial defects is still considered a major clinical

obstacle. In light of this, some investigations have sought to explore the potential of using
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three dimensional constructs having a pre-determined bulk and surface geometry profile. The
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proposed template would, in fact, be primed for inducing the desired cell and tissue growth

orientation in regions that pose considerable rehabilitative challenges. The advent of

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advanced techniques in cell studies and subsequent data generated pertaining to cell

behaviour and metabolism has been of immense importance with respect to devising
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biomaterials tailored to host cellular physiology. This has allowed for great strides in favour
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of eliciting appropriate cell signalling and regenerative cues. Nevertheless, an encompassing

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3D construct that caters to all the criteria essential for the realisation of a functional

restoration of craniofacial tissues in general and the periodontal apparatus in particular such

as the synchronisation of regenerative sequences of multiple tissue phenotypes along with

appropriate spatial organisation of native fibers remains elusive to date [15]. A high level of

tissue compartmentalization exists within the periodontal apparatus. This spatial organisation,

such as the integration of periodontal fibers with neighbouring tissues creates tissue

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interfaces where varying levels of micro – organization translate to adequate physical and

mechanical responses. A diverse portfolio of elaborate microenvironments have been

conceptualised for the restoration of form and function of destroyed tissue complexes as a

result of trauma, tumours and or injury [15]. The periodontal ligament, alveolar bone,

cementum and surrounding structures of tooth present a micro-scale model. Iwata and co-

workers amicably displayed periodontal regeneration via use of stratified and graded cellular

sheets mimicking the periodontal ligament apparatus. They achieved this through the use of

woven poly-glycolic acid merged with porous β- tricalcium phosphate (TCP) [74]. Bottino et

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al., put forwarded the concept of devising functionally graded membranes as the next

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generation of GTR membranes [5]. The concept was applied by Qasim and co-workers (Fig.

6 A and B) to devise different layers of functionally graded membrane that could be combine

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together as one single entity to serve as a GTR membrane. They used techniques of freeze
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gelation and electrospinning and completely characterized each membrane and proposed their

use in a functionally graded structure [37-38]. Electrospinning produces nanofibers with

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unique properties that have been used for a variety of biomedical and dental applications
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[75]. The freeze gelated membranes were fabricated in composite formulations with

hydroxyapatite and used two different solvents.

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7. FGM applied to dental restorative materials

The application of FGM concept in the fabrication of metal ceramic dental restorations has
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been reported by Henriques and co-workers [60,76] as they observed significant

improvement in the performance of such restorative materials. The graded approach

demonstrated higher resistance to contact and sliding, better adhesion of porcelain to the

substructure, improved aesthetics, better fatigue behaviour under loaded conditions compared

to conventional structures [61,77]. Furthermore, the reduction of the thermal stresses at the

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metal and ceramic interface was observed while using these materials. The finite element

analysis demonstrated that the FGM interlayer offered the smoothest profile, with no stress

derivative singularities. [76]. In order to mimic the submicron channels Park et al., [15,78,79]

have extensively studied the fabrication of a spatiotemporally controlled micro-channels.

They adapted freeze casting to control the microscopic patterns of ice crystals and the

regularity of ice growth to obtain unidirectional or radially oriented pores within the internal

microarchitecture of scaffolds [2].

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8. Mutliphasic scaffolds for Bone

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Bone can be best described as a natural polymer - ceramic nanocomposite, interspersed with

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native cellular material, displaying spectra of functional transitions accompanying the

predominant structural motifs. This microstructure is at the heart of the plethora of

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mechanical traits on display such as durability, stiffness, elasticity, tensile strength and

fracture toughness [8]. A structural transition justifies the accompanying subtle change in
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mechanical properties as and when tissue loading requirements vary based on anatomic
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location [9]. There are two known types of stiffness gradients in bone: radial gradients in

long bones and linear gradients in short bones. It would behove investigators to take a leaf
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out of nature’s armamentarium in this case by effectively implementing these naturally

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occurring gradients as part of the development process of future biomaterials. However,

achieving this feat predictably would require a detailed analysis of the underlying chemical
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and structural layout contributing to the gradient itself. Researchers have heavily investigated

the endless possibilities of devising multi-layered scaffolds with continuous interfaces for

bone regeneration in the past [80–84]. A number of different technologies are combined

together to acquire such morphological characteristics. The amalgamation of different

biomaterials at the interface to mimic natural tissue structure and function is the aim of

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researchers so as to target the biological and mechanical requirements of the soft or hard

tissue in question [25].

Rasoulianboroujeni et al., reported a method for designing scaffolds integrated with a

gradient morphology describing a regulated pore morphology conducive to tissue engineering

bone. They were able to harness the pore size using freeze drying technique with a composite

formulation of gelatin with hydroxyapatite (HA) and or tricalcium phosphate (TCP). The

templates fabricated had a porous interconnected structure [85]. A critical key to designing

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smart functionally graded dental biomaterials is to properly capture the degree of complexity

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required to mimic the extracellular matrix of natural oral tissue. An extensive review

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pertaining to the realisation of functionally stacked heterogeneous gradient architecture in

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biomaterials was recently conducted by Liu et al., [26] Spatial ingredients may show a

certain degree of variability at either the bulk or interface of the material (Figure 7). The
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figure shows a broad scale of gradient alterations in which the spatiotemporal properties can
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either have change in a gradual or discontinuous manner. However, with respect to materials

design, the gradients are fundamentally associated with two types of changes: Chemical or
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compositional changes and structural changes such as arrangement, distribution and

orientations (Figure 7c to g). Additionally, interface plays a pivotal role in maintaining

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structural integrity and supporting specific biological functions (Figure. 7h) [1].
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With respect to the commercial availability of functionally graded materials the

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authors feel that by far the clinical setting is still awaiting biomaterials based on functionally

graded interface strategies. Although composite formulations are available in the form of

restorative, endodontic, orthodontic and prosthodontic materials. Clinically used bilayered

membranes made up of collagen ( Jason and Bio-Gide membrane) have been adapted by

periodontists for guided bone and tissue regeneration. These have had limited predictability

with regards to clinical outcome [86].

17
9. Conclusions and future prespectives

An extensive analysis on application of the functionally graded approaches to fabricate

tissue-engineering scaffolds for regeneration of lost oral hard and soft tissues has shown that

there is an immense amount of studies on optimizing or computational modelling using finite

element analysis for studying a graded approach for dental implants. Although majority of

the past research efforts have resulted in high impact publications indicating the potential of

this approach, very few studies have actually “applied” this technique to fabricate scaffolds

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for periodontal tissue engineering. The authors suggest that there is a huge scope of using

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modern additive manufacturing techniques in combination with other template fabrication

methodologies for acquiring graded approach. New frontiers of research should be targeting

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towards biomimicking the natural structure such that the dental prosthesis, restorations,
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orthodontics appliances (fixed or removeable), dental implants and bone scaffolds could be

incorporated with spatiotemporal organization. Proper selection of ideal biomaterials to

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achieve mechanical, biological, functional and esthetic demands of oral and maxillofacial
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templates will play a pivotal role in the future.

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Conflicts of Interest: The authors declare no conflict of interest.

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 315–337.

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Table 1: Studies reporting the fabrication of functionally graded structures to match the morphological variations related to dental landmarks

within the craniofacial region, the technique used and kind of scaffolds adapted to achieve FGM.

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Author date Dental Application Fabrication Technique Biomaterials used /modelling adapted

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Qasim et al., [41,42] Periodontal regeneration Freeze gelation Chitosan Porous templates and micron sized
Electrospinning fibres

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Bottino et al., [43] Periodontal regeneration Electrospinning Fibre guiding scaffolds
Park et al., [2] Periodontal Freeze casting Gelatine
Park et al [15] Periodontal Biomimetic approach Polycaprolactone- polyglycolic acid

Bottino et al., [44]

ed regeneration
Endodontic regeneration Electrospinning Metronidazole/ ciprofloxacin, Polydioxanone
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Watari et al., [45] Dental Implant Cold isostatic pressing and Titanium and Hydroxyapatite
sintering
Kondo et al., [46] Dental Implants Spark plasma sintering Titanium nitride apatite
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Watari et al., [47] Dental Implants Powder metallurgy Titanium cobalt

Watari et al [48] Dental Implant and Dental post Laser lithography Composite resin
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Spark plasma sintering Titanium/ hydroxyapatite

Sazesh et al., [49] Dental implants FGM modelling Titanium Hydroxyapatite
Daniel et al[50] Dental implants Design optimization Computational Bone remodelling
Ichim et al [51] Zirconia Dental implant Finite element analysis Modelling
Shirazi & Asnafi[52] Radial FG biomaterial 3D Finite element simulation Modelling
Henriques et al.,[53] Ceramic metal prosthesis Finite element analysis modelling
Giannitelli et al., [54] Oro maxillary bone regeneration One pot foaming reaction Graded porous

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 t
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Matsuo et al., [55] Dental composite resin post and Laser lithography Composite resin
core
Cui and Jian [56] Ceramic dental restoration Design optimization Finite element analysis

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Henriques et al.,[57] Alumina and zirconia Design optimization Finite element methods
Graded restoration

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Figure 1: (A) Diagrammatic illustration showing the triad of tissue engineering. Cells,
scaffolds and signalling bioactive molecules combination are the basic requirements for
successful regeneration of lost tissue. Adapted with permission from publisher [5]. (B)

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Miyamoto et al., studied functionally graded design, principles and application. Illustration
showed how continuously graded microstructure where the property changes are gradual and
continuous throughout the material [7].
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 t
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Figure 2. Image adapted with permission from Boccaccio et al., [16] representing the

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parametric finite element model of an open-porous functionally graded scaffold was created
in ABAQUS CAEVersion 6.12 (Dassault Systèmes, France). The model has a prismatic

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geometry.
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Figure 3. Diagrammatic illustration showing the general process of selective later sintering
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and 3 D printing as reported by Silva and co-workers.[38] Image adapted with permission

from publisher.
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Figure 4: Diagrammatic illustration of how graded approch can be adapted for dental
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applications
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Figure 5. Watari et al., depicted the expected properties of functionally graded dental

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implants. Image adapted with permission from publisher. The left image shows FGM
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implants and the right image shows conventional uniform implant with the properties being

shown in the middle. [47].

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Figure 6 (a) Diagrammatic illustration of functionally graded concept as reported by Qasim et

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al., using electrospun fibres in different orientation for acting as surface layer to be used in

periodontal tissue engineering using a guided tissue regeneration membrane. The cross-
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sectional image shows how bioactive ingredients can be added with composite structures for
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slow release with time (Image adapted with permission from the publisher)[41]. (b) Freeze

gelated membrane made by composite of chitosan and hydroxyapatite to serve as a core layer
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of a trilayered membrane [42]. (Image adapted with permission from publisher).

35
 t
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Figure 7. Local property profiles and basic forms of gradients in biological materials: (a)
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Local properties change either gradually (I) or in a stepwise manner (II) through the entire

material volume; (b) Local properties vary continuously across the interface between
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dissimilar components; (c–g) The gradients in biological materials are fundamentally

associated with the changes in chemical compositions/constituents (c) and structural

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characteristics, including the arrangement (d), distribution (e), dimensions (f), and
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orientations (g) of building units; (h) Gradient interface in biological materials.

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