one of the most attractive subjects in tissue engineering is the development of a scaffold , a three - dimensional porous solid structure that plays a key role in assisting tissue regeneration .
ideally , a scaffold must be porous , bioactive , and biodegradable and possess adequate mechanical properties suited to the biological site .
sufficient porosity is needed to accommodate cell proliferation and differentiation , which will eventually enhance tissue formation [ 2 , 3 ] .
it is also desirable for a scaffold to have high interconnectivities between pores for uniform cell seeding and distribution , and for the nutrients and metabolites exchange at the cell / scaffold construct [ 46 ] .
a bioactive scaffold promotes cell - biomaterial interactions , cell proliferation , adhesion growth , migration , and differentiation .
it also promotes extracellular matrix ( ecm ) deposition and permits transportation for nutrient and gases and waste removal for cell survival .
a biodegradable scaffold allows the replacement of biological tissues via physiological extracellular components without leaving toxic degradation products .
its degradation rate should match the rate of new tissue regeneration in order to maintain the structural integrity and to provide a smooth transition of the load transfer from the scaffold to the tissue . finally ,
as a mechanical support , a scaffold must possess adequate mechanical stability to withstand both the implantation procedure and the mechanical forces that are typically experienced at the scaffold - tissue interface and does not collapse during patient 's normal activities .
mechanically , the major challenge is to achieve adequate initial strength and stiffness and to maintain them during the stage of healing or neotissues generation throughout the scaffold degradation process [ 3 , 7 , 8 ] .
biodegradable polymers have been widely used and accepted as the most suitable materials for scaffolds due to their degradability , biocompatibility , and ease of processability [ 911 ] .
synthetic biodegradable polymers such as poly(lactic acid ) ( pla ) , poly(glycolic acid ) ( pga ) , and their copolymers have been used in many clinical applications [ 1216 ] .
biodegradable polymers degrade through hydrolysis process and are gradually absorbed by the human body thus allowing the supported tissue to gradually recover its functionality [ 8 , 17 ] .
biodegradability can be imparted into polymers through molecular design with a controlled rate in concert with tissue regeneration [ 1821 ] .
for instance , pla could be combined with pga to form poly(lactic - co - glycolic acid ) ( plga ) , which has degradation rate tailored with the tissue healing period and has been shown to support osteoblast cells attachment and growth in vitro and in vivo [ 2224 ] . beside copolymerization ,
zhang and ma have developed   a highly porous biodegradable polymer / apatite composite scaffold ( 95% porosity ) through a thermally induced phase separation technique , which resulted in significant improvement in mechanical properties compared to polymer - only scaffold .
the work by ma et al .   has shown that osteoblast survival and growth were significantly enhanced in the plla / ha composite scaffolds compared to the plain plla scaffolds .
one of the major concerns regarding the use of biodegradable polymers as scaffold is their poor mechanical properties . for hard tissue applications such as bone , a scaffold that possesses adequate strength and
however , porous polymeric structures are relatively weak and may not achieve sufficient level of the required strength [ 8 , 27 ] . during degradation , polymers could suddenly lose their mass and mechanical integrity .  
figure 1 illustrates mass loss and strength retention as the function of degradation period for some biodegradable polymers used for scaffold .
there is a recent and fast - growing interest in the use of biodegradable metals for biomedical applications .
the inherent strength and ductility owned by metals are the key features that make them appealing for hard tissue applications .
magnesium- ( mg- ) based and iron- ( fe- ) based metals have been used , which include mg - re ( rare earth elements ) [ 2933 ] , mg - ca- [ 34 , 35 ] , pure fe [ 36 , 37 ] , fe - mn alloys [ 38 , 39 ] , and fe foam for bone replacement scaffold .
mg and its alloys have been proposed for orthopaedic implants due to their supportive physical properties to human bones .
it has a density closer to that of natural bones ( 1.82  g / cm ) and has been reported to support the activation of bone cells .
mg degrades in vivo through electrochemical process , which produces mg hydroxide and hydrogen gas . combining their excellent mechanical properties and degradability , mg and its alloys
therefore , this paper aims to review the potentiality of porous biodegradable metals as material for hard tissue scaffold .
elaborations to their rationale , structure , mechanical properties , degradation , and fabrication method are presented .
mg is largely found in bone tissue , it is an essential element to human body , and its presence is beneficial to bone growth and strength [ 5254 ] .
it is a cofactor for many enzymes and serves as stabilizer of dna and rna structures . with
approximately half of the total estimated 25  g content stored in bone tissue , mg is the fourth most abundant cation in the human body [ 56 , 57 ] . in the extracellular
fluid , the level of mg ranges between 0.7 and 1.05  mmol / l , and its homeostasis is maintained by the intestine and kidneys [ 52 , 53 ] .
the incidence of hyper - mg is rare due to the efficient excretion of the element in the urine [ 52 , 56 ] .
mg can be considered as osteoconductive and bone growth stimulator material as suggested by many studies .
a significant increase of bone area has been observed in mg - based implants compared to those based on pla [ 41 , 58 ] .
the corrosion layer around mg implants has been observed to contain calcium phosphates , which appeared to be in direct contact with the surrounding bone .
xu et al . have shown   new bone formation around mg - mn - zn implants in their in vivo degradation in rats .
observed   that 3 months postoperatively , open porous mg scaffolds implanted in rabbits were largely degraded , foreign body giant cells phagocytizing the remaining corrosion products were rarely found , and no osteolytic changes were found around the implant site .
it has been shown that porous mg has better degradation behavior in terms of lower ph change , slower hydrogen evolution , and slower decrement of compressive yield strength in simulated body fluid ( sbf ) immersion tests .
reported   an increasing bone cell adhesion on mg - enriched alumina as expressed by enhanced level of a5b1 integrin receptor and collagen extracellular matrix protein .
two studies using mg - enriched apatites or collagen materials showed good biocompatibility on bone cell attachment and tissue growth [ 63 , 64 ] . mg and its alloys are very lightweight metals having density ranging from 1.74 to 2.0  g / cm , which is less than that of ti alloys ( 4.44.5  g / cm ) and is close to that of bone ( 1.82.1  g / cm ) .
they have a wide range of elongation and tensile strength from 3% to 21.8% and from 86.8 to 280  mpa , respectively .
mg possess a greater fracture toughness compared to that of ceramic biomaterials , and its elastic modulus ( 4145  gpa ) is closer to that of the bone compared to other metals .
mg also has better ductility than synthetic hydroxyapatite and higher strength than existing biodegradable polymers .  
table 1 shows the mechanical properties of pure mg compared to other metals and to bones .
the elastic modulus of pure mg is closer to that of cortical and cancellous bones , which is a superior feature for bone scaffolds .
mechanical property of mg can be further improved by alloying and thermo - mechanical processes .
addition of alloying elements such as aluminium , silver , indium , silicon , tin , zinc , and zirconium could improve both the strength and elongation of mg alloys .
moreover , some manufacturing processes such as hot rolling , hot extruding , and equal - channel angular pressing ( ecap ) could also contribute to the strength of mg alloys and in some cases also improve ductility [ 6769 ] .
in physiological saline environment , mg and its alloys degrade through the following electrochemical ( corrosion ) process [ 65 , 74 ] : 
 ( 1)mg(s)+2h2omg(oh)2(s)+h2(g)(2)mg(s)+2cl(aq)mgcl2(3)mg(oh)2(s)+2cl(aq)mgcl2 + 2oh(aq ) 
 in the first reaction , gray mg(oh)2 film is developed on the surface of mg as it reacts with water and hydrogen bubbles are also produced .
the metal can also directly react with chloride ions to form mg chloride ( 2 ) .
this highly soluble mgcl2 is also formed through the reaction of mg(oh)2 with chloride ions , as depicted in ( 3 ) .
unfortunately , pure mg corrodes very quickly in physiological solution . this may cause mg implant to lose its mechanical integrity before the tissue is completely healed .
moreover , its corrosion reaction produces hydrogen gas at a rate that is too high to be dealt with by the host tissue [ 41 , 76 , 77 ] .
this issue , along with the development of stainless steels in 1920s   led to the abandonment of mg in spite of some early successful implantation results [ 76 , 78 , 79 ] .
as the science and technology of mg processing advances , many improvements have been reported to corrosion resistance as well as to mechanical properties of its alloys . as an example , stroganov et al . reported   that mg alloyed with 0.44  wt% res , and other trace elements such as cd and al , had a slowed corrosion rate , where 3  mm diameter pins resided for 5 months , and those 8  mm in diameter resided for 11 months in vivo .  
table 2 summarizes some reports on various treatments to mg and its alloys for biomedical applications .
have shown   that direct osteogenesis had taken place in the porous particles of hydroxyapatite rather than the solid particles in rat ectopic model .
titanium implants recovered from sheep tibiae showed enhanced cortical shear strength from porous titanium coating , while further coating with hydroxyapatite beads did not result in significant improvement .
although porosity will diminish the bulk properties of a material , porous mg still has the strength and stiffness in close range to that of native bone .
the effects of porosity and pore size on the mechanical properties of porous mg scaffolds have been investigated [ 91 , 92 ] and the results indicated that yield , compressive , and flexural strength as well as young 's modulus decreased with both the pore volume , and size .
pore morphology , volume and size can significantly affect the mechanical properties of porous mg materials [ 91 , 93 , 94 ] .
however , this is not critical for mg scaffolds since their mechanical properties are still comparable to bone [ 95 , 96 ] . the lower limit of bone strength is about 3  mpa , whilst the compressive strength and young 's modulus of cancellous bone are 0.280  mpa and 0.012  gpa , respectively .
hence , the range of bone stiffness and strength may be achieved by mg scaffolds by modulating their porosity and pore sizes .
zhuang et al . had evaluated   in vitro degradation behavior of two different mg porosities in physiological saline solution ( 0.9% nacl ) .
the specimens with 55% porosity degraded faster than those with 36% porosity due to more connecting areas and transport channels for the solution to perform faster chemical reactions .
porous architecture of mg scaffold has been proven to play a significant role in cell growth and proliferation .
tan et al . reported   their work on three - dimensional open - cellular mg structure fabricated by mechanical perforation method . by using the taguchi method , they concluded an optimum pore configuration at 70% porosity , 300  m pore size , and 90 pore arrangement angle whereas these three parameters had different effects on the compressive properties .
pore distribution also influences rabbit cranial bone ingrowth behavior as proved by simon et al . .
they observed a continuous ingrowth in the random pore size scaffolds from the outer periphery ; meanwhile , for the same sized pores and solid walls scaffolds , discontinuous ingrowth with bone islands throughout the whole scaffold was observed . in the recent years , synthesis of cellular metals having open or closed pores of either periodic or random pore topology has been extensively studied .
there have been various routes to modulate the periodic structure topology to satisfy a range of applications including biomedical implants .
random cellular mg can be fabricated via powder or chip sintering ( conventional , laser assisted , or spark plasma ) , low pressure casting , or removable spacer methods .
these fabrication routes generate a random cell structure , wide distributions of cell size , and morphology leading to unpredictable material properties over the range of hundred microns [ 102 , 103 ] .
processes that can be used to fabricate mg with topologically ordered open cell structure include solid free - form process , space holder method , leaching method , replication , electrodeposition , and vapor deposition .   figure 2 shows example of porous mg scaffolds made by two different processes .
this technique encompasses rapid prototyping and casting processes , where a step - by - step fabrication process from computer - aided design ( cad ) models is adopted .
it is currently an ideal solution for manufacturing complex 3d porous structures by accurate controlling of the structure topology .
the six basic steps in the synthesis of a topologically ordered porous mg ( topm ) are ( 1 ) creating a 3d model with the desired architecture using cad ; ( 2 ) printing a positive polymeric template of the model by rapid prototyping ( rp ) process ; ( 3 ) infiltrating the polymeric template with a nacl paste ; ( 4 ) removing the template by heating followed by sintering of nacl ; ( 5 ) casting liquid mg into nacl template , that is , with pressure assistance ; ( 6 ) removing nacl template by dissolution [ 51 , 105 ] .
this technique gives several advantages including the ease of providing considerable high surface area of scaffold , which is essential for cell growth and cell proliferation : also no toxic solvent is involved in the process .
, one of the pioneers in this technique , achieved   high replication accuracy with a resolution of 0.8  mm and errors of 5~12% for their porous mg .
reported   their capability to create square pores with a size of at least 0.3  mm  0.3  mm , and witte et al .
produced   open porous mg scaffolds with 72 to 76% porosity and pore sizes ranging between 10 and 1000  m , and tested into the patellar cartilage of rabbits where new bone formation was observed .
precautions should be taken during the removal process of nacl from the cast mg structure .
the remaining salt will dissolve into aqueous solution and aggressive chloride ions will increase mg corrosion [ 108110 ] . hence , only fresh naoh solution should be used to dissolve nacl to reduce the buildup of chloride ions .
overinfiltrating , partially infiltrating , and underinfiltrating should be avoided so as to obtain a perfect replicate casting of 3d cad model .
it should be noted also that molten mg at high pressure will infiltrate not only pores of the nacl mould , but also the micropores between sintered nacl particles , resulting in the impossibility of the removal of all residual nacl from the structure .
challenge in this technique includes dimensional change from polymer model to nacl template to mg structure .
nguyen et al . reported   dimensional change between 0.3 and 0.4  mm for strut sizes converted from rp model to nacl template as a result of low filling efficiency during nacl infiltration process .
it was also identified that the use of nacl is limited by the strength or fragility of the sintered nacl template , which then limits casting capability . the use of larger nacl particle distribution size ( i.e. , from 20 to 65  mm ) has been suggested to improve the flow of nacl paste and the strength of sintered template .
resolution of the rp printer is also another limitation to produce finer structures at a size similar to the hierarchical structure of human bone .
the limitation in obtaining homogenous pore size by powder metallurgical method can be solved by the use of space holder materials [ 9193 ] .
as an example , carbamide ( co(nh2)2 ) has been used as a spacer material to fabricate porous structures of pure mg .
the process produced open - cellular mg ( porosities : 3655% ; pores : 200400  m ) having mechanical properties close to that of natural bone .
the leaching method has been applied to produce porous mg - calcium - phosphate ( mcp ) , where macropores and micropores were created by nacl particles and saturated nacl solution , respectively .
electrodeposition involves the use of metallic ions solution to deposit metallic elements on electrically conductive polymeric foam ; meanwhile vapor deposition uses chemical reactants in gaseous phase , which were heated by radiation prior to their deposition on polymeric precursor substrate .
fe is an essential element that plays significant roles in human body metabolism including transport , activation , and storage of molecular oxygen , reduction of ribonucleotides and dinitrogen , and decomposition of lipid , protein , and dna damages .
fe has a higher elastic modulus ( 211  gpa ) compared to that of mg ( 41  gpa ) and its alloys ( 44  gpa ) and 316l stainless steel ( 190  gpa ) [ 116 , 117 ] .
are among the first who proposed   fe as a biodegradable metal , where they reported an in vivo implantation test of fe stents in the descending aorta of rabbits .
they showed evidence that pronounced inflammatory response and systemic toxicity were not observed up to 18 months of the study .
have studied   fe foam coated with calcium - phosphate for bone replacement scaffold where human mesenchymal stem cells proliferated and differentiated more on coated fe foams than on uncoated ones .
the coating gave enhanced bioactivity and inhibited degradation of fe foams ; however , the latest is actually questionable since fe was generally viewed as having too slow degradation for implant applications .
the open porous fe and fe - phosphorous alloys have been investigated as biodegradable bone replacement , and the results showed that addition of phosphorus increased compressive yield up to 11  mpa , higher than that of pure fe of 2.4  mpa , and resulted in a young 's modulus of 2.3  gpa which is comparable to that of typical bone .
the alloys showed also faster in vitro degradation than pure fe but still considered slow as large fraction of material was observed during 12 months in vivo study .
nevertheless , alloying fe with phosphorous seems to be a promising way to optimize both mechanical and degradation properties of fe especially for bone scaffold .
porous fe has been fabricated via several methods including solid - gas eutectic solidification process [ 120 , 121 ] , co - co2 gas foaming powder metallurgy process , or powder metallurgy with the use of polymer foaming agent [ 119 , 123 ] , or even using wood as template .
however , those techniques hardly provide the topologically ordered porous as desired for bone scaffold .
moreover , owing to its very high melting temperature , the solid free - form method as applied to mg seems to be nonapplicable for fe where the excessive heat might destruct the nacl template .
biodegradable metals as tissue scaffolding materials have been viewed as alternative to polymers for hard tissue regeneration exploiting mostly their superior mechanical properties over biodegradable polymers .
biodegradable metals such as mg and its alloys possess mechanical properties in close range to those of native human bone and have shown encouraging results when used as tissue scaffolds .
porous fe could also be viewed as a potential scaffold material but available data is scarce especially in its relation to bone tissue . among many promising techniques to fabricate metal scaffolds ,
solid free - form is currently viewed as the most potential method to fabricate biodegradable metal scaffolds having optimized pore morphology for cell growth and cell proliferation .
this technique permitted the design and realization of topologically ordered porous mg with periodic structure for enhanced mechanical efficiency and function of a porous scaffold .
further investigations are needed in the solid free - form fabrication method to develop a scaffold with properties specifically tailored for cell regeneration and tissue growth .
overall , application of biodegradable metals for tissue engineering scaffold is just in the beginning .
the directions could be in finding suitable process for making porous structure from all prospective biodegradable metals , understanding the influence of porous structure to mechanical and degradation properties , and understanding the cell regeneration and degradation product transport in the porous structure .
 scaffolds have been utilized in tissue regeneration to facilitate the formation and maturation of new tissues or organs where a balance between temporary mechanical support and mass transport ( degradation and cell growth ) is ideally achieved . 
 polymers have been widely chosen as tissue scaffolding material having a good combination of biodegradability , biocompatibility , and porous structure . 
 metals that can degrade in physiological environment , namely , biodegradable metals , are proposed as potential materials for hard tissue scaffolding where biodegradable polymers are often considered as having poor mechanical properties . 
 biodegradable metal scaffolds have showed interesting mechanical property that was close to that of human bone with tailored degradation behaviour . 
 the current promising fabrication technique for making scaffolds , such as computation - aided solid free - form method , can be easily applied to metals . with further optimization in topologically ordered porosity design exploiting material property and fabrication technique , porous biodegradable metals could be the potential materials for making hard tissue scaffolds . 
1. Introduction
2. Porous Mg as Scaffold Material
3. Porous Fe as Scaffold Material
4. Perspective