Contents lists available at ScienceDirect Biomaterials Journal homepage: www. Isevier.com/locate/biomaterials ELSEVIER Review Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review ‘Xiaojian Wang *', Shanging Xu *', Shiwei Zhou *, Wei Xu”, Martin Leary °, Peter Choong ‘, M. Qian ”, Milan Brandt °, Yi Min Xie *"* {cenre for nove Stucae nd Materials, Schoo Engen. RT User, CPO Box 276 Mou 3001. itera Asta ® Cen for date Manaacring Schoo of Engineenng RMIT Uniest. CPO Bat 247, Melbourne 30 Vc Ausao “Deparinet of Surgery, University of Mourne Ven Hepa Melnure 3001, Viton, ‘ite ron ‘he ofthe crtial sues In orthopacdie regenerative medine Ir the design of bone safolés and im Receved 2 J 2015 plants that replicate the biomechanical properties of the host bones. Porous metals have found them- Selves to be suitable candidates for repaiting or replacing the damaged bones since ther stifness and porosity can be ated on demands. Another advantage of porous metals is in their open space forthe fnogrowth of bone tssue, hence accelerating the osseointegration process. The labrialion of porous tmetals has been extensively explored aver decades, however ony linted controls over the internal atchitectte can be achieved by the conventional processes, Recent advances in adative manuactuning have provided unprecedented opportunities fr producing complex structures to meet the increasing éemands for implants with customized mechanical performance. At the same tzse, topology optimi= 31 December 205 fected? Jay 2016 ‘ale oan assay 2016 Reyworts deve manaactring Bove send ation techniques have been developed to enable the internal architecture of porous metals to be Ferovs merle Gesigned to achieve specified mechanical properties at wil Thus implants designed via the topology Dethepaeeemptnts ‘optimization approach and produced by additive manufacturing sre of great interest. This paper reviews Booster the state topological design and manufacturing processes of various types of porous metals, Jn particular for titanium alloys, biodegradable metals and shape memory alleys This review also ‘denis the imitations ofcurent techniques and addresses the directions for future investigations (© 2016 Elsevier Le, Al rights reserved. 1. Introduction tissue creates the morbidity associated with a second surgical site {An alternative choice is allograft tissue (taken from another per- Bone is a complex tissue that continually undergoes dynamic biological remodelling. ie, the coupled process whereby osteo- clasts resorb mature bone tissue followed by osteoblasts that generate new bone to maintain healthy homeostasis of bone [1] This unique Featute of bone underpins its ability o remodel tse to repair damage. However, when abone defect exceeds a critical non- hhealable size, external intervention is required to supplement self healing ithe defects to be bridged [2 Despite recent advances in biomaterials and tissue engineering, repair of such a eritical-sized bone defect still remains a challenge. The optimal choice isto use autograft (patients own tissue) [2], However, harvesting autograft * Cvsesponding auth Cee fr tnovativeSrutures and Mates, schol o Engineering, AMIT University, GP0 Hox 247, lboure 300, Vito Astras. Ema dre; ioe (VM i) qual contusion. 142-9612 2016 Elsemer a. Al ihts reserve. son), which carves the risk of transmissible disease and depends on Togistic circumstances (limited availablity). The insuffciencies of application of autograft and allograft tissue have led to greater research efforts to identify biomimetic materials and structures that are suitable for skeletal repair without the inherent problems ‘Metals and alloys have a long history of application as bone implants [47], Among them, the use of stainless steels, cobalt (Co) based alloys (CoCrMo), and titanium (Ti) and its alloys are well established due to their good biocompatibility, satisfactory me- chanical strength and superior corrosion resistance [5], However, implants made of these materials are usually much stifler than natural bones, leading to stress shielding ~ a major source for bone resorption and eventual failure of such implants (5), Cortical bone (compact bone) has elastic moduli ranging from 3 to 30 GPa, while {trabecular or cancellous bone has significantly ower elastic modull of 0.022 GPa. Most current implant materials have much higherbs X Wang eal Someta 832015) 127—14 ‘moduli than those of bones, eg, TISAI4V has a modulus of around 410 GPa and CocrMo alloys have a modulus of around 240 GPa [5.58]. Thezefore, to avoid stress shielding at the bone-implant Interface, the equivalent Young's modulus and yield stress have to be adjusted when using these bulk materials. An effective method is to introduce adjustable porosity or relative density as proposed by Gibson and Ashby (9] for isotropic materials. Traditional methods for fabricating open-cell porous metals include liquid state processing (direct foaming, spray foaming, etc), sold state processing (powder metallurgy, sintering of powders and fibres, etc), electro-deposition and vapour deposition (10,1) Although the shape and size of the pores can be adjusted by changing the parameters of these manufacturing processes, only randomly organized porous structure can be achievable. However, additive manufacturing (AM) technologies can fabricate porous metals with predefined external shape and internal architecture [2.12—14], Metal-based additive manufacturing (MAM) techniques, such as selective laser melting (SLM) and electron beam melting (EBM), are computer controlled fabrication process based on layer- ‘wise manufacturing principles. SLM [15~17| and EBM [15,19] are increasingly used for the fabrication of porous metals with complex architecture. Instead of using electron beam as the energy source in EBM, the SLM technology uses laser beam with adjustable wave- length. Therefore, EBM can only process conductive metals whereas SLM can process polymer or ceramics as well as metal Furthermore, due to more difuse energy (larger heat-affected zone), EBM process has larger minimum feature size, median powder particle size, layer thickness, resolution and surface finish [20), The robust application of MAM technologies requires exten- sive material, process and design knowledge, specific to each MAM technology [21]. MAM system behaviour is subject to significant stochastic error and experimental uncertainties, requiring that assumptions are necessary to simplify the problem” [22|, Sources of error include: complex and transient heat transfer phenomena [23], geometric effects [24) with poorly defined powder thermal properties [25]. MAM prediction error can lead to excess melt pool temperature [26], resulting in undesirable microstructure, residual stress, local porosity, and surface roughness, Understanding the effects of design decisions on temperature related process defects is critically important to the process control. Comprehensive reviews of AM technologies can be found elsewhere [27.28 Recent suceesses in orthopaedic regenerative medicine have promised an exciting future of AM technology. The world's frst additively manufactured mandible was implanted in 2 patient by Dr, ules Poukens and his team in 2012 in Belgium 29) A fll lower jaw implant (mandible in Fig. 1) was coated with hydroxyapatite and implanted in an 83 year old lady. The porous implant was slightiy heavier than a natural jaw, and provided robust attachment of muscles and. sufficient space for nerves [29]. Skull re- constructions with AM parts have been performed successfully by using digital design and AM. Mertens et al. [30] successfully reconstructed a class Ill defect using AM manufactured titanium implants, which provided both midfacial support and a grat fixture (rmidface defect in Fig. 1), Jardiniet al [31) in Brazil designed and ‘AM fabricated a customized implant forthe surgical reconstruction. ofa large cranial defect. In 2014, Prof. Peter Choong, an Australian surgeon Irom St Vincent's Hospital, together with scientists from the Commonwealth Scientific and Industrial Research Organization (CSIRO) and Anatomics successfully implanted the world’s first 30- printed titanium heel bone into a patient (32), ‘Typical design and application approaches of porous metallic implants normally include the design of scaffold, AM and post- processing (heat-treatment and surface modification) as illus- trated in Fig. 1 Ths review aims to identify the current status and the future directions of design-oriented AM technology” in producing porous metallic structures for bone tissue repair, with a Particular emphasis on topological design of internal architecture of porous metals for bone implants 2, Structure and properties of bone 21, Structure of bone Bone is a natural composite containing both organic compo- nents (mainly type-t collagen, but also type-I type-lV collagen and frillin) and inorganic crystalline mineral (eg. hydroxyap- atte, HA) [122.35,34), as illustrated i fig. 2. The structute of bone is similar to reinforced concrete that is used in the building industry. The function of HA crystals and collagen molecules are like the steel rod and cement to concrete: one part provides Alexibikty and the other provides strength and toughness, Type-1 collagen is 2 triple helix of -15 nm in diameter and -300 nm in length. itis the primary organic components of bone. Other non- collagenous proteins include glycoproteins and bone specific proteoglycans ||. Hydroxyapatite is the inorganic component of bone and is plate-shaped of 50 x 25 nm in size and 54 nm thick [35], The HA crystals are oriented in a periodic array in the fibrils, preferentially with their c axis parallel to the collagen fi- brils (35). These two phases account for about 9 wt. % of the dry bone Bone has a hierarchical structure. Each level performs diverse ‘mechanical, biological and chemical functions. The hierarchical levels of bone include macroscale, microscale, sub-mictoscal, nanoscale, and sub-nanoscale (Vig. 2). The macroscale level rep- resents the overall shape of the bone. Bone can be classified as compact bone (cortical bone), and trabecular bone (cancellous bone). Compact bone is almost solid, with only -2—5% spaces for osteocytes, canaliculi, blood vessels, and erosion cavities etc ‘There are large spaces in trabecular bone. The pores in trabecular bone are filled with bone marrow, and the porosity varies be- tween 50 and 90% |1,36~38], The building block of compact bone is the osteons, which are of the size ranging from 10 to 500 ym, whereas the trabecular bone is made of a porous network of trabeculae. At the micron- and nano-scales, aggregated type-l collagen and HA form the collagen fibril, The reinforced collagen fibre is a universal building element for both compact and trabecular bones. 22. Mechanical properties of bone Mechanical properties of bone vary significantly with age, anatomical site and bone quality. t continues to be a major scien tific challenge to fully understand the mechanics of living bones [35-38]. Among the various biomechanical properties of bone (stitiess, strength, creep and fatigue) elastic modulus has attrac- {ed the most reseatch interest because ofits critical importance for characterizing various bone pathologies and guiding artifical implant design. The elastic modulus and strength of bone are anisotropic. Compact bone is both stronger and stiffer when loaded longitudinally along the diaphyseal xis than the radial transverse directions (Table 1). It is also stronger in compression than in tension, Trabecular bone is an anisotropic and porous composite. Like many biological materials, trabecular bone displays time- ependent behaviour as well as damage suscepribility during cy- lic foading (41). The mechanical properties of trabecular done epend on not only the porosity, but also the architectural arrangement of the individual trabeculae. The physical and me- chanical properties of human bone ate summarized in Table 1 (values are averaged from reported data) [1.26,34,36~28,42,43]A Wang ea Someta 832015) 127— 40 ns Scaffold design + CAD based + Image based (MRUCT) + Imp surface + Topology optimization rail defect 1) Heat-treatment + Postheattreatment + Insitu hestteatment ‘Surface modification ++ Coatngrbased + Coresiontbased Orthopaedic regenerative medicine Fig 1. Schemas dara forthe design, ave manaactrng, hestesimet race madeton of prour mete stacey and the tet othepaeéc resentative elcine examples ages adaped oo Rel [20-10 Macrostructure Microstructure | Nanostructure | Sub-nanostructure ig. 2, Herarchcl structural ezanization Boe. age apie fram Res. [35.3940 23, Requirements for the design of orthopaedic implants ‘A successful porous metallic implant would restore the function ‘of bone and promote regeneration of bone tissue at the damaged site, AN ideal bone scaffold should possess the following characteristics: (1) biocompatibility: (2) suitable surface for cell attachment, proliferation and differentiation: (3) highly porous with an interconnected pore network for cell ingrowth and trans- port of nutrients and metabolic waste: (4) mechanical properties to ‘match the requirements of the surrounding tissues to reduce orbo X Wang eal Someta 832015) 127—14 cai peopestes of human bones, average vals Hom berate 12654.35-38.42 3) Perot eau (oP) Seach PT Tecan ato rabecla fone uptosox Vera 057 = 0048 dass eliminate stress shielding, and to meet anatomic loading re- quirements to avoid mechanical failure 448), Porous metals are implanted to repair bone defects of critical size and, in mast cases, serve as load-bearing devices. Bone is usually anisotropic with diferent stfiness and strength in different directions, bt normally there are no extremely weak directions (49), Therefore, suitable porous metals will approximate the sti ness of surrounding bones, making them effective for load transfer and alleviating the stress shielding effect ‘The key characteristics to design porous metallic implants include the careful selection of porosity, pore size, and pore inter- connectivity, aiming to achieve satisfactory clinical outcomes. These structural features have a profound effect on mechanical properties and biological performance of the metalic implants Bone regeneration in porous implants in vive involves recruitment and penetration of cells from the surrounding bone issue and vascularization [50]. Higher porosity may facilitate these processes and benefit the bone ingrowth. For instance, more bone ingrowth ‘was found in porous titanium coatings of higher porosity alter the implants were placed into a canine model for & weeks (SI). Simi= larly, one ingrowth was shown to be deeper and greater in porous polymer scaffolds of higher porasity [52 “The influence of pore size on the bone ingrowth is still contro- vversial in literature 5357), The optimal pore size for mineralized bone ingrowth is claimed to be 100400 ym in the research by tala et al. [53]. They implanted triangle-shaped titanium implants of, diferent plate thickness with pore size ranging from 50 to 125 jm inco rabbit femur and found that there was no clear lower limit of| pore size for consistent bone ingrowth [53], Recently Braem etal [5] assessed the feasibility of early bone ingrowth into a pre- dominantly microporous Ti coating in the compact bone of rabbit tibiae and found that new bone formed in micropores of less than 10 um. Large pores are believed to favour vascularization. Bai etal, [55] suggested an upper limit of pore size for vascularization, 400 tam, beyond which no significant cifference was observed with increasing pore size. Kuboki eta, (54 found that, when the pore size ranged from 300 to 400 ym, the implantation of porous hy- Aroxyapatite scaffolds into rats showed higher alkaline phosphates activity, osteocalcin content and bone ingrowth. However, Naoya et a. [57] implanted 300 jm, 600 ym and $00 ym AM manufactured porous T scaffolds into rabbit tibia and they found 600 ym and 800 tm scaffolds demonstrated significant higher bone ingrowth than 500 yim scaffolds. In addition to vascularization, specific surface area of scafolds is another essential factor with respect to fixation ably. Seaffolds with smaller pores are considered to have larger surface area and therefore mote space for bone tissue ingrowth, ‘Another important feature of bone implants isthe permealality of the porous metal since the transportation of cells, nutrients and growth factors require the flow of blood through the porous scaf- folds. In simple terms. permeability is characterised by using gradient pressure to push liquid through porous material. Zhang et al, [58,59] stated that permeability may influence vascular invasion and the supply of nutrients required to sustain cell growth and may also provide an outlet for the removal of cell debris, thereby increasing its asteoconductive potential. High permeability of ‘titanium implants enhances the osseointegration process [8.59]. Further research on the effect of permeability of porous ‘metallic implants is in demand, In summary, porosity, pore size and pore interconnectivity are key factors that will significantly influence the mechanical prop- erties and biological performance of scaffolds such as bone ingrowth and transportation of cells and nutrients. However, the effects of these factors on scaffold performance are complicated, even conflicting to each other in certain circumstances. For example, increasing the porosity may enhance the biological pro- cesses, but it can decrease the sifiness and strength drastically [9] ‘Therefore, Gnding the optimal topologies for scaffolds is of critical importance. However, conventional CAD-based design techniques are inefficient and usually fail to obtain the optimal scaffold design because a prohibitively large number of trials would be required in order to achieve a balanced performance, e, desirable stiffness and good permeability, On the contrary, topology optimization techniques are capable of quickly finding the optimal topologies which satisfy multiple objectives and constraint simultaneously 0 provide site-specific biological performance, 3. Topological design of porous metallic structures for orthopaedic implants 31, Porous metallic implants and topology optimization techniques ‘As mentioned previously bone is a3D inhomogeneous structure with elaborate features from macro-to nano-scales. While it is impossible, and perhaps unnecessary, to recreate all details of natural bone in the porous metallic implant, ideally the implant should have similar hierarchical configurations on multiple scales. Icis essential thatthe implant should possess properties similar #0 the host bone and the ambient tissue [60], This calls for a well- established design methodology integrating structural stiffness With fuid permeability to allow the implant to have both adequate rigidity to resist the physical loading and suflicient permeability to transfer cells, nutrients, etc. Fully solid metas, eg. titanium, are unsuitable because they ate inherently impermeable, preventing cells from invading inside to proliferate and form extra cellular ‘matrix. Moreover, the Young's modulus of human bones (Table 1)is ‘muich lower than that of sold metals. Such astifness mismatch is regarded as one of the most significant problems in implant design as the resulting stress shielding would often lead to implantation failures. Recently, porous metals were used in orthopaedic surgeries to replace damaged bones. Porous scaffolds are geometrically similar to natural hard tissues which are composed of constituting ma- terials penetrated by interconnected pores (61), Porous metals can be designed to duplicate the properties of bones if thei structuresX Wang ea Someta 852015) 127— 40 (brary of Platonic and Archimedean payieral oi LOS DOS S928 POH HES a i a| ‘ 1) 69 @E® ° 4 tg ‘ier CAD sofware generate design RR 4 Topelogy Optimization 106) ro 10] fo] tra Fie 3. Approaches or sll design: representative unit els and Mes. mages aapied fom Rel, 452~94,7.727480106-108, could be designed digitally and fabricated using advanced ‘manufacturing technology. Conventional porous scaffolds typically consist of a vast number of randomly shaped pores in different sizes and therefore itis almost impossible to quantitatively analysem A Wang etal Someta 852015) 127-14 their properties. To obtain a simplified model, researchers usually assume that scaffolds are constructed of periodically-repeating Unt cells along all directions and the architecture of the micro tnt cells can distinctly define the macro properties of the scaf- folds. Typical traditional design strategies of periodic bone scaf- folds include Computer Aided Design (CAD), image-based design and implicit surfaces (62, as illustrated in Fig. 3. CAD-based design are obtained by using vatious CAD tools. The widely used library of constructing units always involves Platonic and Archimedean polyhedral solids, which can also be used to construct functional graded scaffolds [53~55]. Computer-aided system for tissue scaf- folds (CASTS) isa further development based on these scaffold i- braries, aiming to eficienty automate the entre design process for desired topologies 5759]. Bio-inspired design isan alternative to improve the mechanical performance of bone scaffolds and enrich the scaffold library [70=72|, Other CAD-based approaches may also be used in designing scaffolds [14). Image-based design, as proposed by Hollister et a. [73] is based on Computed Tomogra- phy (CT) or Magnetic Resonance Image (MRI) data for recon struction ofa defect t uses Boolean combination of defect image and architecture image (could be from empirical or bio-inspired shapes) to create 3D scaffold image [12.7275]. Implicit surface ‘modelling uses single mathematical equations to freely introduce pore shapes such as triply periodic minimal surfaces (TPMS), Which is highly flexible in designing scaffolds (62.7080), CAD- based randomization approach starts from cel elements to fil a specific volume in computer software, where standard cell ele- rents are usually packaged while new cell elements can also be created (81,52), This method can effectively imitate real bones by the randomization process, thus promoting the bone attachment and bone cell in-growth, as well as increasing the damage tolerance, ‘While the aforementioned methods enable scaffolds to obtain desirable stifiness and permeability, these approaches demand a ‘vast number of attempts to achieve anticipated properties. Often. the resulting design is far from the optimum. One of the main challenges in the application of porous scaffolds to orthopaedic implants is the adaptation of their mechanical and biomedical properties to those of natural bones, The implanted scaffolds are placed in a complex environment and their performance is affected by many factors. Some of them such as high permeability and good stiffness are competing with each other since a larger pore size is obtained usually at the cost of a lower mechanical stength (82. Hence, to increase the mass transfer, while retaining a strong supporting framework, there isa need fo maintain a delicate trade= off between the porosity ofthe fabricated scaffold and its strength [10 ‘Topology optimization ~ a mathematical method capable of, rearranging the materials to attain desired properties while satisfying prescribed constraints ~ can complement the trial-and- ertor approach and provide a powerful tool to design complex scaffolds with features on multiple scales. It is @ branch of computational mechanics and was originally developed in struc- tural engineering [84]. It has been widely used for designing structures and materials for desirable mechanical performance and physical properties. Through two decades of development, this ‘method has gone far beyond the traditional structural engineering context [35 ‘Typically, there are two ways to define a structure in topology optimization, The first is a point-by-point description in which a ‘void (p 0} orasolid(p - 1) phase in a local element is represented by an elemental density p (86). The Evolutionary Structural Opti- mization (ESO) |8788] and the Solid Isotropic Material with Penalization (SIMP) methods [85,89] use this type of description and have gained considerable success in solving a wide range of engineering optimization problems. Inthe field of computational ‘material design, the topology optimization approach is termed as an “inverse homogenization” method because the homogenization ‘method [90.91] is used to calculate the effective properties of a unit cell and the material distribution is rearranged thtough topology ‘optimization to enable the material to attain target properties. The seminal work of inverse homogenization was conducted by Sig- rmund in the 1990s for the design of materials with prescribed clastic properties [92,93]. Thereafter, great achievements were obtained in the design of exceptional material properties including negative thermal expansion coefficient [94 and negative refraction index [95], Later, this method was extended to the design of scaf= fold materials with their stfiness matrices matching those of anisotropic native bones (75,9597). By using the SIMP based structural optimization, Guest and Prevost [98] developed a to- ology optimization technique to fing a scaffold with pores in the shape of a Schwartz primitive structure, resulting inthe maximum permeability. They also combined bulk’ modulus and permeability in a single objective function and tailored these two competing properties in a multi-physies optimization problem [99]. Using a similar density-based optimization method, scaffolds with elastic ensors similar to those of natural bones were designed; and the performance of these scaffolds in subsequent tissue ingrowth was investigated (100), 11 is found that bone remodeling is at its best When the scaffold elastic tensor matches or is slightly higher than the elastic properties of the host bone. “The last row in Fig. 3 shows the porous structures with the ‘maximum bulk and shear moduli, respectively, at a given porosity ‘These unit cells were obtained using the Bi-directional Evolu- tionary Structural Optimization (BESO) method (101105), which shows faster convergence and unambiguous material definition [105-109], The BESO method, which allows the material to be added and removed simultaneously during the optimization pro- ess, is an extension of the original evolutionary FSO method proposed by Xie and Steven [87.85 As shown in Fg. 3 on topology optimization, various unit cells with maximal bulk modulus ‘maximal shear modulus, prescribed stiffness ratios in three di- rections. and functionally graded structures can be obtained through the BESO method. ‘The second class of topology optimization methods, represented by the level-set algorithm [110], focus on tracking phase bound aries. In the level-set method, the interfaces of two phases are implicitly defined by the zero-level contour af a high-dimensional level-set function, The level-set method provides an effective technique to represent smooth boundaries and to control topology changes (11 A variational level-set technique for periodic mate- nal design problems governed by Navier—Stokes and Maxwell's equations was developed to attain material with maximal perme- ability [112] Level-set topology optimization enables the no-sip boundary condition of fluids in Stokes flow to be naturally sais- fied [173]. Petiodie structures of scaffolds with the maximal effec- tive diffusivity aimed at providing an ideal environment for nutzient transportation were studied by a level-set based optimi- zation method (114 ‘There have been tremendous advances in recent yeats in the area of using topology optimization techniques to design multi- functional materials with periodic structures, as shown in a comprehensive review by Cadman [1I5). Several of these de- vvelopments are directly related to the design of scaffolds. Both stiffness and diffusive transport properties were considered by Hollister 12.44) and Challis et a. [116]. Using topology optimiza- tion, Hollister and co-workers also created an interbody fusion cage for improved arthrodesis [117]. The outcomes of their research were used in clinic to support bone regeneration for craniofacial reconstruction [12A Wang ea Someta 832015) 127-4 1 32, Constraints structural design for additive manufacturing Although AM can theoretically produce structures in any shape, the quality of the structures may vary significantly depending on the design and fabrication parameters [118]. Therefore. it is necessary to consider the processability of the designed parts during the topological design process, including the constraints and limitations of AM technologies. However, there is stil limited research on creating design guidelines to achieve this goal. Kranz ct al 119] experimentally investigated the restrictions of Laser ‘Additive Manufacturing (LAM) of TIGAIMV and presented a comprehensive structured catalogue, In ther research, restrictions and recommendations were presented based on experimental ‘measurements of different characteristics such as cavities (powder removal, volume reduction), walls (edges, corners and thickness), bores (size, orientation and tooling), gap (dimension, form), hollow cylinder, overhangs and support structures. They also found that the quality of AM parts was highly dependent on the materials, machines and process parameters. Therefore, similar guidelines could be achieved through similar methodology on different ma- terial systems. Among many parameters, frequently discussed one includes overhanging structures, which may lead to some unde- sirable defects [120.121]. In an AM process, the overhanging slructure is nol supported by solidified section or bottom substrate When it is being built. Therefore, the overhanging structure is strongly influenced by the orientation of building (Fig. 4 (a}-(4)) [121], Therefore, the critical fabrication angle sof great importance since it determines the form of overhanging structure, hence the processability (120, Fig. 4 (e) [120] shows the sketch of a circular Pore with overhanging arc AB, which can be processable if the fabrication angle were larger than the critical value 4,. Otherwise, supporting structures have to be used, which are normally avoided to prevent damage of parts in post-processing. A better choice in design isto adopt structures with special geometrical arrangement such as an octahedral latice, whose lateral schematic is shown in Fig. 4(0)(120]. When the downward sloping susface CD has a larger fabrication angle than the critical angle 0, no supporting structures @ (b) Downward faces Fabrication direction are required, ‘There were also attempts to design structures so that they could be fabricated using AM without support [122|. This approach is interesting and useful, but may not be generally applicable to scalfold designs. Other reseatchers examined the suitability of us- ing SIMP and BESO topology optimization algorithms to design structures for AM (122) 4, Current status of AM and topology optimization in, producing porous metallic structures, AM technologies are superior to conventional fabrication tech- siques for producing porous metallic implants with complex and customized structures, as shown in Fig. 5. In addition to the geo- metic flexibility, composites with two or more phases can be ‘manufactured. These advantages enable AM to become a promising tool for the production of biomedical implant devices, controlled drug delivery systems, and enginected issues 124-125), Examples {nclde artificial joints and load-bearing implants produced by AM using biocompatible materials such as hydroxyapatite, i, Ta and Co=Cr—Mo alloys [2,44,127.134) and customized prostheses such as intervertebral spacers [135]. There has been growing research in- terest in using topology optimization to design bone scaffolds and orthopaedic implants [75.95~100,136—144], however significant challenges still remain before these concepts could be used in clinical practice. An important issue that may not be neglected when applying topology optimization to scaffold design is to consider the differences in physica, chemical and mechanical properties of base materials produced by AM and conventional fabrication techniques. The material property in AM process may greatly allect the final topological shape of scafold, which may {ier from the original CAD model abtained from topology opti- ‘mization, Moreover, good understanding of the change in me- chanical properties in AM process may assist more accurate optimal design in topology optimization procedure. Ths section will review the status of research on AM fabrication of three main families of alloys and the application of topology optimization F Fig 4 Examples ef overhanging structs 3) stares having dona sloping ae and (@ austing dead soln laces by changing be airline pst] ocessbly of ceuar pote ane) unptoved design ofa poe images reprogued ot Res. 130121be A Wang ea Someta 83208) 127-141 Fics, rhotsraphs f dave manfred bane sales: TGA plats in sheep cera spin vt-podaced pan i seal (6 nd the sale wih bemegenecus and tick CaP esting 0 {D Seite He eng sett) an he cexesponig eae we) 41, Biocompatible T alloys Metals in biological systems may experience corrosion and release ions, which may result in many adverse physiological ef- fects Therefore, the biocompatibility (defined by the toxicity and carcinogenicity from the release of metal ions) of any implant must be quantified to decrease the patients tisk and the failure of the implantation [4]. The cytotoxicity of typical surgical implant alloys and pure metals have been broadly studied in the past decades Ie is now commonly accepted that vana- dium (V) may cause sterile abscess and aluminium (Al) may cause scar tissue, whereas titanium (7) zirconium (2s), niobium (ND) and tantalum (Ta) exhibit excellent biocompatibility ‘Another important motivation behind the design of biocom= patible Ti alloys is the opportunity to decrease the modulus of Ti alloys by adding f-stabilizing elements, As mentioned above, the f= stabilizing elements should be biocompatible. Various type Ti alloys composed of low modulus biocompatible elements (Le, Ta Nb, Zs, Mo) were developed, These alloys exhibited lower modulus than the commonly used TIGAI4V. One example is TH3ND132r Which showed improved bone biocompatibility and a ‘modulus of 79 GPa. Other §-type Ti alloys which exhibited lower modulus (-5~65 GPa) included Ti29NbI3TE462r and T3SNDSTA7Ze In recent years, AM produced porous Ti alloy scaffolds were widely reported with TIGAI4V in dominance, such as the Ti6Al4V implants in sheep cervical spine in Fig. 5 (a) (135) Ryan eta. combined the multi-stage AM technology with the powder met- allurgy process to produce porous TI alloy scaffolds using wax templates generated by CAD. The pore size oftheir designs ranged fom 200 to 400 jm and the porosity reached 668%. This method could achieve controlled porous structure and ensure high reso- lution in manufacturing. The resulting microstructure and surface roughness were similar to parts manufactured by conventional ‘methods. This method could also he extended to the fabrication of| other metallic structures which are difficult to be directly made by ‘AML Murr et al [14] manufactured different porous TiGALAV m= plants using AM based on micro-CT sean and CAD models built by “Materalise software. They studied the influence of geometric fea- tures of unit cells on the mechanical properties of the porous structures and found that when the porosity changed from 59% to Bx, the elastic modulus decreased from 3.03 to 0.58 GPa, which proved that the elastic modulus of porous metals could be readily adjusted through the porosity. Similarly Pattanyak et al. 17) stud- ied porous Ti implants based on micro-CT scan on human cancel- lous bones, which focused on structures with complicated internal structures for bone ingrowth applications. The implants were manufactured via SLM using Ti powder of less than 45 jum in size They found that the compressive strength decreased from 120 to 35 MPa when the porosity changed from 55% to 75%. Hollander et al. [151] produced a variety of TIGAl4V implants, ranging from pporous eylinder to solid human vertebra model with itregular shapes Porous TiGAI4V structures were shown to be effective inDX Wang / Bimal #2 (2016) 127—140 bs supporting cell growth and new bone tissue growth, and cell based study suggested that TIGAIAV possesses high cyto-biocompatibility [85.152—156].n vitro studies were performed with porous Ti6Al4V structures. Cll spreading and proliferation were observed across the entire surface and inside the porous structure [156]. A similar study was performed by Van Bael etal [155], which suggested that enhanced cell seeding and proliferation were achieved on porous slructures. Porous TIGAIAV scaffolds were found performing wel in animal models since induced new bone growth and osseointegra- tion were achieved on both bare and surface-coated porous TiGAl4V structures (135,152). Although porous TIGAI4V had been widely studied, the potential release of toxic ions led researchers towards looking for safer alternative alloys. Therefore, Ti alloys such 3s ‘Ti24Nb4zr85n, TH.5Mo and TON were designed and fabricated by AM, which exhibited comparable mechanical properties to theit counterparts by conventional manufacturing approaches [157—160], ‘There was significant research interest in using topology opti- ‘mization for the design of porous Ti alloy scaffolds [116 135~144] While early works mainly focused on the theoretical consideration of the structural design of the unit cells, recent efforts put more ‘emphasis on integrating topology optimization (the design aspect) with AM (the fabrication aspect), eg. RefS. [116,136] 42. Shape memory alloys Shape Memory Alloys (SMA) are capable of regaining their original shape after severe deformations when stimilated by external environments |153,154), Due to this unique property, SMAs have found their way in orthopaedic implant applications ‘Typical SMAs include NiTi or nitinol which normally contains approximately 50 at Ni and 50 at% Ti, The shape memory effec in INiTi comes from the austenite!martensite phase transformation since martensite is a low temperature stable phase with the absence of stress whereas austenite is a high temperature stable phase [165.166]. Currently, more than 80% of all commercial SMAS are based on NiTi and its ternary alloys - NiTiCu and NiTiNb [167] Solid NiTt has a modulus of 48 GPa, which is much lower than other Tialloys. Furthermore, NiTi allows for relatively large reversible deformation of up to 8%. Nii has higher stiffness than bone under tendan, and is able to deform over a large strain range at an almast constant stress (plateau stress) | 161,168}. Due to these character- istics, NTi has been widely used in medical devices, such a surgical tools, stents, orthodontic wires. plates and staples for bone frac- tures, ANTI scaffold for pseudoelasic application is shown in Fig, 5 (b) (161), Main attractive features of SMAs are: (1) capability to Fecover the original shape after large deformation (pseudo-elas- ticity), (2) capability to recover the original shape from a stable deformed shape when heated (shape memory effect) and (3)a high damping capacity, For biomedical applications, the presence of Niin NITi has been. 4 continuous concern since Ni is one ofthe highest sensitivities in metallic allergy tests [165,170]. Therefore, attempts were made either to develop surface modification techniques ot to use sub- stitution elements to mitigate this effect without sacrificing the biocompatibility [160,171—175]. For example, TIND and the related TTINOX system (where X — Zr Ta, Hi) were developed which exhibited elastic strains as high as 4.2% (175), Common methods for making porous NIT structures are based ‘on powder metallurgy (PM) and selt-propagating high temperature synthesis (SHS) of a mixture of elemental powsiers (Ni and Ti) or pre-alloyed NiTi powder with space holding materials {175~178} After removing space holding materials at relatively low tempera- tute, the structures are further sintered at high temperature (176-178), Due to high reactivity of Ti and Ni, the sintering of porous structures is normally done in high vacuum, However, these methods have difficulties in precisely controlling the porous structures of NiT, ie, pore size and pore shape. To avercome this problem, AM technologies such as SLM have been used to produce [iT implants [179184], It was shown that AM produced NiT parts exhibited similar mechanical properties as those fabricated by conventional methods such as casting (181.182). ln contrary tothe substantial reseatch on Ti alloys, no reports on the application of topology optimization in the design of SMA scaffolds involving AM fabrication can be found in the literature up todate, 43, Biodegradable metals Biodegradable materials, including both polymer-based and ‘metal-based ones, are used for some medical implants which will aradually degrade in human body over a period of time [185]. In some clinical cases, biomaterials are only needed temporarily inthe body and are expected to support the healing process and to disappear after the healing process is completed. Fig. 5 (c) shows 2 biodegradable Mg stent after expansion [162]. Compared to polymer-based materials, biodegradable metals have higher stiff ress and strength, and are more suitable for load bearing condi- tions. As the degradable alloys (mainly magnesium and iron based alloys) are expected to degrade inside human body, the main compositions of the alloys should be metallic elements that can be ‘metabolized, and demonstrate appropriate degradation tates inthe human body | 185].Due to its unique characteristics, Mgalloys were used to manufacture cardiovascular stents (152| and bone screws [187]. The degradable magnesium allay bone screws were found clinically equivalent to the conventional Ti screws; and no foreign body reaction, osteolysis, or systemic inflammatory reaction were ‘observed for the Mg alloy screws (187) ‘A key parameter that needs to be considered in designing a biodegradable metallic implant is its degradation rate in human body. Pure Mg is known to havea fast degradation in high chloride physiological environment but it may produce hydrogen gas at @ high rate from corrosion, which cannot be dealt with by the host tissue. Fe-based biodegradable materials are known to exhibit 2 slow degradation rate. Animal tests showed that large portions of| the pure Fe stent remained intact in the blood vessels 12 months post-surgery [188], Alloying is a typical method to adjust the {degradation rate of a metal For instance, by adding elements such as ¥ Sr, Zn, Zr and Ca, Mg alloys were shown to have much lower {egradation rates in comparison with pure Mz, Such alloys also exhibited high strength, which is desirable for load-bearing appli- cations. In addition to alloying. amorphous structures like metalic lass alloys MgZnCa showed low degradation rate and high strength [189,190], However, metallic glass alloys are generally dificult to manufacture. which would add the cost tothe applica- tion of this type of material [190], Porous Mg allay implants were investigated as temporary bone replacements in an animal model [181,192], They were shown to be able to enhance bone remodelling and appropriate host response However, porous Mg alloys degrade too rapidly in vive, which may leave subcutaneous gas cavities [193]. Since an open porous implant has large surface area, only alloys with slow degradation rate should be considered for making the porous structure, eg. Mg- 4. The element yttrium helps promote grain refinement. thus resulting in a slow degradation and sufficient cyto-compatibility [193]. Nguyen et al, 194] manufactured porous Mg alloys using SLM and suggested that the dimension, surface morphology and the oxygen pick-up of the laser-melted Mg were strongly depen- ent on the laser processing parameters. Due to the high evapo- ration rate at elevated temperatures, few attempts were made toBs A Wang etal Someta 852015) 127-141 fabricate Mg scaffolds directly using AM [195]. Instead, a technique combining 3D printing and gravity casting was shown to be effec- tive in producing topologically-ordered porous Mg structures [196.197], where a porous NaCI mould was created using SLM and then Mg alloy was cast into the mould. After removing the Natl porous Mg structure with porosity of 41% and pore size of 1 mm Was obtained, The compressive strength of the porous Mg was re- ported to be 13 MPa, which is comparable to porous Mg produced by powder metallurgy 197) ‘A review on porous biodegradable metals for hard tissue staf- folds can be found in Ref. 198]. A theoretical study of topological design of polymeric scaffolds considering the elfect of biodegra- dation was conducted by Chen et al, 199), No reports on the application of topology optimization in the design of biodegradable metallic scaffolds involving AM fabrication have appeared in the literature so far 5. Heat-treatment and surface modification of porous metallic structures produced by AM Si. Heat-treatment The mechanical properties of AM produced materials depend heavily on the processing parameters, including building layer thickness, scan speed, energy density and focal offset distance [200.201], Usually AM (SLM or EBM) produced materials have relatively high yield stress (Ti6Al4V, ~1000 MPa) and ultimate tensile strength (TIGAIAV, -1150 MPa), but a relatively low ductility (TiBAIAY, less than 10%) [200,207.203), In arder to improve the ‘mechanical properties of AM produced porous biomaterials so that they can mimic the human tissues and fulfil the desired functions, post-treatment is of critical importance. It is known that the mi- crostructures of as-built materials by AM are very different from those by traditional casting or forging approaches. AM is a layer- ‘wise build-up process with high cooling rates that lead to signif cant internal thermal stresses inthe structure, During the building process, the scanning by either a laser (for SLM) of an electron beam ((or EBM) may cause the instabilities of the melt pool, resulting in increased porosity and high surface roughness [200.204). Therefore, heat-treatment for changing the microstruc- tures is routinely applied in most applications to meet the product requirements. The post-treatment process also enables the reduc~ tion of thermal stresses in AM produced structures. For TIGAIAV, post heat-treatment is typically performed within the « +d region (where «to phase transition temperature T;s 995 °C), which can Control the morphology and size of the a-phase without signif- cantly influencing the priot-f grain size. Heat-treatment above Tz leads to a complete dissolution ofthe a phase and the coarsening of prior-6 grains [200]. A proper heat-treatment process may sub- stantially improve the mechanical properties of AM produced materials. Thone et a. [205] observed significant improvement in ductility and fatigue strength after heat-treatment of SLM produced TTIGAIAV. They revealed that the tensile strength of heat-treated ‘TIGAIAV slightly decreased from 1080 MPa to $45 MPa but the elongation at failure increased significantly from 16% to 116%, along with remarkably prolonged fatigue life of parts from 28,900 to 290,000 cycles (205). The improvements in the mechanical properties after post heat-treatment are mainly due to the elimi- nation of thermal stresses and the changes of microstructures. On the other hand, an adequate selection of AM processing variables can facilitate in-situ heat treatment, The microstructure of TSAI4V made by SLM is often dominated by a’ martensite due to rapid cooling, which can be decomposed to lamellar « 4 6 structure during SLM process by tuning the processing variables [201]. After the optimization of processing conditions, Xu et al. 201] produced ‘TIGAIAV with comparable or better mechanical properties chan. forged TIGAIAV. 52. Surface modification Surface modification plays an important role in enhancing the biological performance of AM produced porous biomaterials, particularly bioactivity and biocompatibility [205-212]. alleys are normally covered by one layer of 3-7 nm thick native oxide, rnamely TiO, which provides excellent chemical inertness, carro” sion resistance and biocompatibility. in the human body, Ti alloy implants may experience non-specific protein adsorption and interrogation of neutrophils and macrophages, which may attract fibroblasts to an encapsulation process, To ensure an effective biological bond between T alloy implants and surrounding bones, surface modification is essential to improve the conductivity of bones or the bioactivity of titanium [7213]. The surface ‘morphology of 7 alloy implants depends on the history of material processing. For AM produced porous Ti alloys, powders tend to become small liquid spheres when heated up by laser or electron beams [18]. Such a “balling” effect is a complex metallurgical pro- cess that leads to a rough surface and residual powder particles [179}. These loosely connected powder particles can be removed through blasting or other post-processing methods before implantation, ‘Surface modification or activation of Ti surface can be achieved by various techniques such as plasma spray, physical or chemical vapour deposition, ion implantation, electrochemical oxidation, acidic or alkali etching, sol-gel, heat-treatment, and. surface ‘machining or grinding, For porous metallic structures, there are two main approaches, based on surface coating and surface ‘A popular coating-based method is sol—gel process, which is a simple yet versatile method for creating oxide coatings a relatively low temperatures. For implants with a complex topology, dip coating is normally used, The sol-gel process may deposit thin (<10 jm) inorganic coatings. The chemical composition and mi- ‘crostructures ofthe coating can be better controlled by the sol~gel process than by other methods. Other advantages of the sol process include homogeneity and low cost. Brie et al. [214] used sol-gel to form a bioceramic coating (CaP) on porous TiSAI7Nb implants. The coating uniformly covered the external and internal surfaces of the implants; and the coated porous structures exhibi- ted improved biocompatibility. ther methods include electrolytic epasition (ED) and plasma spray. ED can produce CaP coatings hhaving a thickness of a few microns to several hundred microns, ‘which can be controlled by applying appropriate current density, and processing time [152). This may also assist to control the sur- face morphology of CaP coatings from needle-like to plate-like structures. Coating through ED can produce uniformly and ful covered surface, which makes i suitable for functionalizing porous structures. Chai etal. [152] found that the bioactivity of the CaP coated TIGAIAV scalfold (surface morphology is shown in Fig. 5 (d) to (e)) was significantly improved and it was possible to produce steoinductive “bio-units” lor the repai of bone detects, Corrosion-based surface treatment involves interfacial chemical reactions of structures in corrosive solution, Such chemical pro- cesses include alkali treatment [215~217], aid etching (179) and anodization treatments [218.219] Fis. 5 (h) to (i) show the surface ‘morphology of scaffold before and after HCI etching treatment [18] ‘The chemical reaction may produce a thin oxide layer (of TO, for example) on the surface of the metal, usually resulting in improved bioactivity. The thickness ofthe active layer can be controlled from {ens of nanometer to hundreds of microns by adjusting processing Variables. Alkali treatment was initially introduced by Kim et alA Wang ea Someta 832015) 127— ur [215] to improve the bioactivity of T1 implants owing to a biologi- cally active Done-tike apatite layer on Ti surface. Anodization is a ‘mature electrochemical process capable of producing protective layers on the metal surface with adjustable surface microstructure and crystal structure [218,279]. Special cate should be taken with regard to the possible negative effect on mechanical properties aller corrosion-based surface treatment. It was reported that alkali {eeatment might result in the deterioration of mechanical strength of porous Ti alloy scaffolds and also eause the embrittlement of the struts in the scaffolds [209) 6. Challenges and future directions Additive manufacturing provides unprecedented opportunities for producing customized medica implants as this technology can fabricate structures of complex external shapes and intricate in- ternal architectures. Topology optimization has become a powerful digital tool for the design of optimal structures and materials. The integration of these two technologies sees a promising future in designing and manufacturing biocompatible orthopaedic implants with desired mechanical properties and minimal side effects on patients in clinical applications. Key challenges and future di- rections in integrating the two technologies are as follows: 4) A.comprehensive and reliable database containing detailed information on the mechanical and biological properties of hhuman bones is yet to be established, This database should include properties of bones for diferent age, gender groups and at different locations, Such information is required asthe design “target” of the topology optimization process. ii) Sophisticated topology optimization algorithms capable of dealing with multi-functional designs on multiple length scales simultaneously needs to be developed. Preliminary studies along ths line can be found in Refs. [220.221] iil) Topological design of the lattice structures that can be easily produced by AM and exhibit anisotropic mechanical prop- ‘erties similar to human bones is another promising directio ‘despite thatthe fact that there has been extensive research, ‘on Copology optimization based on continuum models. 'v) Constraints and limitations of current AM technologies, such, as the critical angle of the overhanging structure and the difficulty in removing the supporting structure, should be involved in newly-developed topology optimization algo- rithms so that the “optimized” designs could actually be fabricated by AM, -v) The long-term in vivo materialfbiological performance of Porous metallic implants that are designed through topology optimization techniques and produced by AM needs to be rigorously assessed in order to ascertain the advantages and “drawbacks of such implants, vi) Novel alloying systems capable of enhancing the mechanical and biological performance of porous metalic implants are in great demand, together with new post-treatment tech- nologies for improving the bioactivity and biocompatibility. 7. Conclusions In this paper, the current status of the topological design of porous metallic implants anc the fabrication of such implants Using additive manufacturing is reviewed. First the mechanical proper- ties of human bones are discussed, Then itis demonstrated that topology optimization is a powerful digital tool that can be used to obtain optimal incernal architectures for porous implants which ‘not only satisfy multifunctional requirements but also. mimic ‘human bones. Furthermore tis shown that additive manufacturing 's the most promising and disruptive technology in the fabrication of porous orthopaedic implants designed through topology opti- ‘ization, To further improve the mechanical and biological per- formance of these structures, both post-treatment and surface ‘modification are necessary. Based on these discussions, challenges and future directions of the integration topology optimization with additive manufacturing are identified. This review provides useful information to researchers and practitioners who ate working in Various areas of the truly mulidseiplinary topic of bone implant design and fabrication. ‘Acknowledgements ‘This work was supported by the Australian Research Council (0P140100213 and LP140100607). References, 1B cues, Roe: See ané Machin, Fon Univeay 1S ahd Banton enseeg se 1 Fauna sect or tt and peeves vas ket Spel Roe Batty of ay fa og 1 Seti ts tr Rm a 8G (ofan Sand erp ann lye (Sia che cag Ste modmy and ‘eed ma bone spose 5 eR 200 (OLE eve, 10, ruey CE suai, KA Ga, KE, Watden 4, cminhum me efit plant a 0 veer oe fens sane ntl Spe 91st 11 en ny ear Ss Se ne ropes, Candie Shorey es ti) ayn kode Apatdabcin metas of pore met Selig pion ber 3 a) 25a tun Jahre tana chan sn pp of cet mete tome ane fog Mate 5 01 Sela ti Stine Fen ei fr oe ee Na Mae 4 13) San Bae, Kerekhots, M Maesen. Fak.) Sebrosten JP ruth Mier (14) LE Mure, SMC Gaytan, F Medina HL Lopes, F Mastines. 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