A review on the mechanical and biocorrosion behaviour of iron and zinc-based biodegradable materials fabricated using powder metallurgy routes

1 Introduction

1.2 Fe and Zn as biodegradable material in physiological environment

Both Zn and Fe are necessary trace elements that are crucial to the functioning of the human body. Despite their relatively low quantities of necessity, their roles are essential for general health and well-being. Fe has a major role in oxygen transport, cellular respiration, energy production, DNA synthesis and immune function whereas Zn aids the enzyme functions, immune systems, wound healing, reproductive health, taste and smell receptors, growth and development of bones and muscles. The recommended dietary allowance (RDA) of Fe and Zn along with the upper intake level is provided in Table 1. The over and below consumptions of Zn (Levy et al. 2017) and Fe (Frossard et al. 2000) can lead to multiple illness and health complications as shown in Figure 1.

Figure 1:

Illness and symptoms associated with excess and deficiencies of Fe and Zn (Frossard et al. 2000; Levy et al. 2017; Mezzaroba et al. 2019; Plum et al. 2010; Shankar and Prasad 1998).

When pure Zn is exposed to body fluid, a layer of ZnO/Zn(OH)₂ is produced on the surface following the chemical reaction given in Equations (1) and (2). The presence of Cl⁻ ion in high concentration in the body fluid cause the dissolution of ZnO/Zn(OH)₂ surface film by converting them into soluble chloride salts as per Equations (3) and (4). Prolonged exposure of Zn in physiological environment (pH = 7.3, T = 310 K, E = 0.78 V) results in the formation of calcium phosphate and zinc carbonate along with ZnO. Liu et al. (2019) studied the effects of bovine serum albumin (BSA) on the in-vitro breakdown of pure Zn in artificial plasma during 28-day immersion period. It was reported that the corrosion process took three steps in the presence of BSA. Figure 2 depicts the corrosion of pure Zn in artificial plasma, comprising all three stages. These stages included: (i) BSA adsorption, which protected the substrate from dissolution (Day 1), (ii) BSA and Zn²⁺ chelation, which accelerated the corrosion rate (Day 3–7), and (iii) improved corrosion resistance due to the accumulation of corrosion products (after Day 7).The Pourbaix diagram of Zn (Krężel and Maret 2016) shows the presence of Zn²⁺ ions over 7–8 pH range and 0.8 V to −0.76 V potential range indicating the active nature of corrosion (partial/no protection from surface corrosion products) as confirmed by Thomas et al. (2012).

(1) Formation of Zn ( OH ) 2 : 2 ( Z n 2 + ) + 4 ( O H − ) → 2 Zn ( OH ) 2

(2) Formation of ZnO : Zn ( OH ) 2 → ZnO + H 2 O

(3) 6 Zn ( OH ) 2 + Z n 2 + + 2 C l − → 6 Zn ( OH ) 2 ∙ ZnC l 2

(4) 4 ZnO + 4 H 2 O + Z n 2 + + 2 C l − → 4 Zn ( OH ) 2 ∙ ZnC l 2

Figure 2:

Illustration of the corrosion process of Zn in artificial plasma: (a) adsorption of BSA at the initial stage; (b) dissolution of Zn; (c) formation of a complex of BSA and Zn(OH)₂/ZnO; (d) accumulation of the complex on Zn surface. Reprinted from Liu et al. (2019) with permission from Elsevier.

Similar to the case of Zn, a complete passivation cannot be achieved in the case of pure Fe in Cl⁻ ion containing environment. The equilibrium chemical reaction of iron in Cl⁻ ion rich environment given by Tolouei et al. (2016) can be seen in Equations (5)–(11). The degradation product may vary depending upon the type and concentration of different ions i.e., HCO₃ ⁻, HPO₄ ⁻/HPO₄ ²⁻ present in the test medium (Salama et al. 2022; Tolouei et al. 2016).

(5) F e 2 + + 2 C l − ↔ FeC l 2 + H 2 O ↔ Fe ( OH ) 2 + HCl

(6) 4 ( Fe ) + C l − + 8 ( H 2 O ) ↔ F e 4 ( OH ) 8 Cl + 8 ( H + ) + 9 e −

(7) 4 ( F e 2 + ) + C l − + 8 ( H 2 O ) ↔ F e 4 ( OH ) 8 Cl + 8 ( H + ) + e −

(8) 4 ( F eOH + ) + C l − + 4 ( H 2 O ) ↔ F e 4 ( OH ) 8 Cl + 4 ( H + ) + e −

(9) F e 4 ( OH ) 8 Cl ↔ 4 γ − FeOOH + C l − + 4 ( H + ) + 3 e −

(10) γ − FeOOH → dry F e 3 O 4

(11) γ − FeOOH → Fe ( III ) → α − FeOOH

2 Powder metallurgy processes for Fe and Zn-based implant fabrication

The powder metallurgy route for producing biomedical implants offers flexibility over casting route in terms of porosity control (Čapek et al. 2015), complex shape manufacturing (Lewis 2013), reduced waste and near net shaping (Alam et al. 2020). Casting produces highly dense implants with slow degradation rate, making them suited for fabrication of permanent implants having a high service time within physiological environment. In contrast, powder metallurgy creates porous implants that improve tissue integration and vascularization. This method also allows for faster, controlled degradation, beneficial for rapid resorption needs. In addition, powder metallurgy allows for greater design and material customisation, potentially lowering production costs and environmental impact. The sintering process is an integral part of the powder metallurgy manufacturing technique that is used to form solid objects from powdered materials without reaching complete melting stage. It involves heating the powdered material to a temperature below its melting point but high enough to promote diffusion, particle bonding and densification. The powder features such as size distribution, shape and minor element concentration can affect the final porosity in the final specimen which can directly affect the mechanical and corrosion properties irrespective of the use of same sintering route. A narrow powder size distribution with a smaller average particle size has known to yield better packing density, thereby enhancing the mechanical strength and reducing defect (Shon et al. 2014). Further, some studies (Clares et al. 2022; Manchili et al. 2021; Oh et al. 2016) reported that the use of bimodal powder mixture can result in improved sintered density which can be explained with the help of German’s prediction model (German 1992). According to this model, designing powder mixtures for maximum sintered density is critically related to the large and small powder shrinkage. A high density can be expected in a bimodal system containing large particles with higher sintering shrinkage and small particle with relatively lesser sintering shrinkage. Particle shape also plays an important role as it can affect the particle packing density. Irregular powder particle exhibits greater interparticle friction which can lead to poor powder packing, resulting in inferior quality of sintering. Hence, a pressure assistance is provided before (pressure-based densification) or during the sintering process (hybrid densification) involving irregular powder particle. On the other hand, spherical powders have excellent powder packing characteristics and can be sintered without pressure due to their large surface area. However, relatively high level of porosity can be expected while dealing with pressureless sintering which can reduce the mechanical properties and increase the corrosion rate due to infiltration of corrosive physiological fluids within the pores. Besides, powder shape and size distribution, the presence of minor elements can significantly affect the mechanical and corrosion properties due to the formation of intermetallic or undesired phases. Hence selection of precursor powder is also important in powder metallurgy. On the basis of the type of heating mechanism and application of pressure the sintering process used for Fe and Zn-based material can be broadly classified into three categories as mentioned below.

2.1 Conventional sintering

In a conventional sintering setup, an electrical resistance-based heating mechanism (Lee et al. 2023) is used to heat the heating chamber in which the green compact is placed. Tube furnace and muffle furnace are two widely used furnaces that employ resistance-based heating. The schematic diagram for the tube furnace can be seen in Figure 3. In the case of a tube furnace, the electrical heating coil surrounds the exterior of the refractory tube providing uniform and direct heating to the sample within the tube. On the other hand, a muffle furnace incorporates indirect heating of the sample through convection and radiation (Oghbaei and Mirzaee 2010). The atmosphere of the heating chamber in both the cases can be controlled with the use of various gases for specific applications. To avoid oxidation of the sample during sintering, an Argon protective atmosphere should be maintained within the heating chamber. These categories of furnaces are cheaper but the prolonged sintering cycle arising from slower heating rates can cause grain coarsening which can directly affect the mechanical and corrosion properties of fabricated samples.

Figure 3:

Schematic representation of a tube furnace.

2.2 Microwave sintering

Microwave sintering incorporates microwave radiation of frequency 2.45 GHz to facilitate internal volumetric heat generation required for sintering. This process utilizes the dielectric loss of a material in a microwave electromagnetic field to generate heat by converting the electromagnetic energy into thermal energy (Cheng et al. 2022; Mehta et al. 2023). The volumetric internal heating of the specimen helps in obtaining high heating rates ranging from 5-100 K/min. The faster heating rates augmented with uniform heating significantly reduce the duration of the sintering cycle (Salehi et al. 2021). The energy consumption in the case of microwave sintering is significantly lesser (nearly 9 times) as compared to conventional sintering owing to difference in sintering mechanism and shorter cycle time (Demirskyi et al. 2011; Salehi et al. 2019, 2021). However, the sintering efficiency of the final product depends on the type of material to be sintered. Microwave absorbers such as ceramics are best suited for microwave sintering whereas bulk metals are opaque to microwave at room temperature. Powdered metals can absorb microwave radiation to a certain extent at room temperature and the absorbance increases with an increase in the temperature (Agrawal 2013, p. 362). Hence, to improve the heating of green specimens of Fe and Zn at room temperature, microwave susceptors made up of ceramics are placed inside the casket cavity surrounding the green compact (Das and Pandey 2024) as depicted in Figure 4a. This step ensures the heating of the sample at low temperature by establishing two-directional heating as shown in Figure 4b. Microwave sintering produces finer grain size compact owing to shorter heating and holding time. However, the cost of the microwave furnace is higher than that of conventional sintering furnaces.

Figure 4:

Schematic representation of (a) hybrid microwave sintering setup and (b) bi-directional heat flow in the sample in hybrid microwave sintering.

2.3 Spark plasma sintering

Spark plasma sintering (SPS), also referred to as field-assisted sintering technique (FAST) is a hybrid sintering technique that densifies the product by simultaneous application of heat and pressure (Guillon et al. 2014). This process involves the direct passage of pulsed or unpulsed direct current or alternating current through the graphite die containing the powder compact along with the application of pressure to obtain the final product (Figure 5a). The internal heat generation by Joule heating facilitates achieving very high heating rates of upto 1,000 K/min, reducing the overall sintering time to a few minutes. The uniformity in current distribution over the die and compacted powder affects the sintering quality which can be seen in Figure 5b. The high speed of the sintering process effectively minimizes the grain coarsening which assists in producing nanostructured metal, alloys and composites yielding exceptional strength and corrosion resistance (Herrmann et al. 2010). Metastable phases such as phases present in multi-principal element alloys can be preserved using this technique (Das et al. 2022b; Shkodich et al. 2022). However, the cost of the SPS furnace and associated tooling is significantly higher than that of conventional furnaces and microwave furnaces. A complete comparison between the three types of sintering furnace is summarized in Table 2.

Figure 5:

Schematic representation of (a) SPS process, (b) schematic current flow diagrams for (b1) conductive die and powder, (b2) insulating die and conductive powder, and (b3) conductive die and non-conductive powder (Guillon et al. 2014).

Table 2:

Comparison between conventional sintering, microwave sintering and spark plasma sintering.

Name	Heating type, principle	Heating rate (K/min)	Holding time (min)	Advantage and drawbacks
Conventional sintering	External, resistance heating	1–20, Peroglio et al. (2022)	120–600, Kumar and Pandey (2020)	Low capital investment, high sintering cycle time, excessive grain growth
Microwave sintering	Internal, dielectric loss	5–100, Gunnewiek and Kiminami (2014); Singh et al. (2018)	10–90, Gunnewiek and Kiminami (2014); Singh et al. (2018)	Moderate capital investment, less sintering cycle time, minimize grain growth
Spark plasma sintering	Internal, Joule heating	5–1,000, Sharma et al. (2019), p. 30	∼2–30, Sharma et al. (2019), p. 30	High capital investment, least sintering cycle time, minimize grain growth

3 Mechanical, biodegradation and in-vitro biocompatibility behaviour of iron-based material

Iron-based materials have high strength-ductility, which is necessary for their usage in orthopaedic applications. However, the density and elastic modulus mismatch with the bone can give rise to the problem of stress shielding. In this regard, the powder metallurgy technique can be beneficial as control over both the density (by adjusting porosity) and elastic modulus can be achieved through this manufacturing route. The comparison of mechanical properties of Fe-based alloys/composites fabricated by the PM route can be seen in Table 3. The in-vitro corrosion rate which is affected by the exposed surface area, porosity, and type of element present is also reported in the same table. The data presents a wide range of variations in mechanical properties depending on the type of PM route and post-processing technique. The spread of elastic modulus in the range of 0.16–56.6 GPa indicates the flexibility of the PM process over the casting process as the elastic modulus of as cast Fe-based material is in the range of 100–210 GPa (Feng et al. 2016; Marshall et al. 1982; Xu et al. 2015). Xu et al. (2015) compared the mechanical properties of Fe–28Mn–xSi (x = 0, 2, 4) fabricated by two different routes i.e. casting + forging and compaction + conventional sintering. In both cases, UTS and Young’s modulus (E) increased with the increase in the amount of Si in the alloy. However, the UTS and E values showed by PM samples (156.6–362 MPa, 77.58–88.55 GPa respectively) were remarkably lesser than that of the forged sample (682.48–847.55 MPa, 158–163.58 GPa respectively) owing to the presence of porosity in the sintered specimen. A closer inspection of the fracture morphology of the tensile specimen revealed the presence of voids which were the main reason for brittle fracture in the case of PM fabricated Fe–28Mn–xSi alloys. On the other hand, the presence of porosity favoured accelerated corrosion kinetics in the PM sample more than its forged counterpart regardless of Si content. Other elements such as Ag, Pd and Mg were also alloyed with Fe in literature to enhance its corrosion rate. From two independent studies conducted by Čapek et al. (2016) (employing conventional sintering) and Čapek et al. (2017) (employing SPS) on Fe–2Pd alloy, it can be concluded that the in-vitro corrosion rate of Fe–2Pd alloy tested in SBF is higher than that of pure Fe irrespective of the type of PM process used. However, both studies showed contrasting results on the effect of mechanical properties on Pd addition. The study that employed conventional sintering (Čapek et al. 2016) exhibited a decrease in mechanical properties whereas the study involving SPS (Čapek et al. 2017) reported an enhancement in mechanical properties with the addition of 2 wt% Pd to pure Fe. In general, the YS and UCS of Fe–Pd alloy should increase owing to the second phase strengthening effect as the solid solution strengthening is expected to be non-significant due to negligible lattice distortion (Huang et al. 2014). Also, incorporation of SPS can aid in reducing the porosity and restricting the grain growth which can improve the strength of the sintered Fe–Pd specimens simultaneously. The explanation for the decreased mechanical properties of Fe–2Pd in the case of conventional sintering (Čapek et al. 2016) can be related to the existence of a high volume % of porosity (19 ± 1.4) in comparison to the Fe–2Pd sample manufactured by SPS (5 vol %) (Čapek et al. 2017). Apart from alloying, Fe-hydroxyapatite (HAP) metal matrix composites (MMCs) were fabricated by Dehestani et al. (2016) by using conventional sintering and Tripathi and Pandey (2023) by employing pressureless microwave sintering. Specifically, the study reported by Dehestani et al. (2016) assessed the effect of HAP loading and HAP particle size on yield strength, tensile strength and in-vitro corrosion behaviour of Fe-HAP MMCs which can be seen in Figure 6. Increase in the HAP content from 2.5 to 10 wt% and lowering the HAP particle size from 100 to 200 µm to <1 µm resulted in a reduction of mechanical properties and an increase in the corrosion rate (refer to Figure 6 for the values). From the above observation, it can be inferred that when the amount of HAP in a matrix material is increased while the size of the HAP particles is decreased (which results in a greater surface area of HAP), the Fe–HAP interface regions, as well as the size and number of defects associated with those regions, are also increased, which led to higher corrosion rates. Also, incorporation of ultrafine HAP particles (<1 µm) in Fe matrix resulted in improper interfacial bonds, causing porosity in the sintered specimen which acted as penetration sites for physiological medium. Recently, hydrogen evolution was observed during the in-vivo and in-vitro testing of Fe–35Mn–1Ag alloys (Dargusch et al. 2021) similar to that of Mg alloys. However, the volume of evolved H₂ was significantly lesser than that of Mg alloys.

Figure 6:

Effect of HAP content and its size on (a) tensile strength, (b) corrosion rate obtained from potentiodynamic polarization and (c) corrosion rate obtained from immersion test for 21 days in Kokubo’s solution. Reprinted from Dehestani et al. (2016) with permission from Elsevier.

As Fe is not FDA-approved, the biocompatibility evaluation of the Fe-based material manufactured by powder metallurgy is critical. To this end, Paim et al. (2020) reported the in-vitro biocompatibility analysis of 99.5 % and 99.95 % pure Fe fabricated through the PM route with Adipose-derived mesenchymal stromal cells (ADSCs). The study incorporated both indirect cytotoxicity test and a direct culture of ADSCs on the surface of sintered specimen. The cell viability of both the samples determined through MTT assay at two different time points i.e., 24 h and 48 h showed good cytocompatibility even with the 100 % extract. In addition, the sulforhodamine B (SRB) assay confirmed that the iron extracts did not hinder the proliferation potential of ADSC cells. The study also confirmed the slightly haemolytic nature of Fe-based material (haemolytic index: 1.46–5.327 %). Wegener et al. (2011) evaluated the effect of individual addition of multiple elements such as C, P, B and Ag to Fe on its cytotoxicity behaviour with fibroblasts. Under the static testing condition, rapid cell death was observed for pure Fe and Ag containing Fe whereas the P and B containing Fe exhibited a limited cell growth over 5 days. The dynamic test conducted in a perfusion bioreactor (continuous exchange of culture medium while keeping the cell in the bioreactor) also showed the similar trend of cell growth. Huang et al. (2016) used SPS to incorporate Ag and Au into the Fe matrix in varying wt% (2, 5, 10) to enhance the galvanic corrosion of Fe due to presence of nobler Ag and Au. The maximum corrosion rate evaluated by potentiodynamic polarization in Hank’s solution was 0.1746 mmpy which corresponds to Fe–10Ag. The relatively lower value of corrosion rate can be ascribed to the absence of porosity which is supported by the stated relative density (∼98.5 %) of all samples. The study also evaluated the cytotoxicity (indirect assay) of Fe–Ag and Fe–Au composites by using L-929 murine fibroblast cells, human vascular smooth muscle cells (VSMCs) and endothelial cells (EA. hy-926) obtained from the human umbilical vein. All of the experimental material extracts had no substantial toxicity on the L-929 and EA. hy-926 cells, however they did reduce the proliferation of vascular smooth muscle cells significantly. The as-sintered Fe-based material exhibited good antiplatelet adhesion properties as compared to as-cast pure iron. Xu et al. (2016) investigated the biocompatibility of frequently used Fe–Mn-based alloys (Fe–28Mn and Fe–28Mn–3Si) fabricated by conventional sintering. The indirect cytotoxicity test indicated no adverse effect of corroding ions on L929 cell proliferation. However, the presence of Fe²⁺ and Fe³⁺ ion in excess can escalate the production of reactive oxygen species such as hydroxyl radicals ( OH ˙ ) through Fenton and Haber-Weiss reaction. As per the Fenton reaction (Beaufay et al. 2020), the Fe²⁺ can react with hydrogen peroxide to form OH ˙ and as per Haber-Weiss reaction (Wang et al. 2021), Fe³⁺ can react with superoxide radicals ( O 2 − ˙ ) and hydrogen peroxide to generate OH ˙ . The OH ˙ can contribute to oxidative stress by oxidizing wide range of biomolecules which results into cellular damage. Hence, a high free Fe ion concentration in physiological environment should be avoided for biosafety reasons.

4 Mechanical, biodegradation and in-vitro biocompatibility behaviour of zinc-based material

Pure Zn fabricated from the casting route suffers from low mechanical strength as well as limited ductility due to the absence of enough slip systems at room temperature (Hermawan 2018; Tong et al. 2018). Pure Zn prepared by different sintering techniques exhibited mechanical strength in between the range of 33–171 MPa which can be seen from Table 4. The Zn sample prepared by SPS showed the highest strength of 171 MPa (Yang et al. 2018) owing to the advantages associated with the SPS process. Hot extrusion of the compacted Zn also showed a high tensile and compressive strength of 156 ± 5 MPa and 215 ± 4 MPa respectively due to the presence of bimodal grain structure having equiaxed grains of size 10–30 µm and elongated grains of 50–300 µm length and 10 µm thickness (Kubáse et al. 2019). Alloying Zn with other elements such as Mn, Mg, and Fe results in the formation of second phases, which improves the mechanical characteristics of Zn. Bagha et al. (2018) synthesized nanocrystalline Zn–4Mn and Zn–24Mn by employing high energy ball milling and conventional sintering in a tube furnace. The Zn–4Mn alloy exhibited a compressive strength of 290 MPa due to the presence of MnZn₃ and MnZn₁₃ intermetallics in the microstructure. However, the addition of 24 % of Mn led to formation of intermetallics in high volume fraction which adversely affected the strength and failure strain. Also, the addition of Mn lowered the corrosion rate significantly due to the presence of intermetallic phases. The cytotoxicity evaluation involving the L929 cells demonstrated a decrease in the cell viability with increasing the exposure time due to the accumulation of ZnO particles in the media. Despite the reduction in cell viability with time, both Zn–4Mn and Zn–24Mn exhibited permissible cytotoxicity (grade 0–1) as per ISO 10993-5:2009 (2009). Similarly, Li et al. (2023) fabricated a series of Zn–xFe (1, 1.5, 2) alloys by employing SPS which resulted in the formation of FeZn₁₃ intermetallics. Also, the addition of Fe promoted grain boundary pinning phenomena which resulted in grain refinement. The compressive yield strength increased from 96.1 MPa for pure Zn to 135.2 MPa for Zn–1.5Fe due to the combined strengthening effect arising from grain boundary pinning and precipitation strengthening which can be visualised in Figure 7. However, the addition of Fe beyond 1.5 wt% resulted in decreased mechanical properties due to the high-volume fraction of intermetallic phases. The potentiodynamic polarization study indicated a shift of corrosion potential (E _corr) towards more negative side and increase in corrosion current density (i _corr) value with the addition of Fe resulting from micro-galvanic mode of corrosion. The CCK-8 assay in Mg-63 human osteosarcoma cells performed on Zn–1.5Fe alloy extract showed a slight level of cytotoxicity (cell viability >85 %) which can be classified as 0–1 grade cytotoxicity. Besides alloying, reinforcing the Zn matrix with bioceramics such as HAP can improve the mechanical properties as well as biocompatibility. Incorporation of HAP in the Zn matrix prepared by microwave sintering (Pathak and Pandey 2020, 2021) in the range of 1–5 wt% significantly enhanced the compressive yield strength of the MMCs owing to the effective load transfer mechanism at matrix-reinforcement interface. However, the addition of HAP beyond 5 wt% significantly reduced the compressive yield strength arising from HAP agglomeration and weak interfacial bonding. Yang et al. (2018) also fabricated Zn–xHAP(1, 5, 10 wt%) metal matrix composite by employing a different sintering approach i.e. SPS. In contrast to the results published in (Pathak and Pandey 2020), this study reported a decrease in compressive strength with the addition of HAP particles to Zn matrix. The contrasting effect of HAP addition documented in (Pathak and Pandey 2020; Yang et al. 2018) can be related to the measured density of the MMCs which is a direct measure of porosity. The MMC samples fabricated by Yang et al. (2018) showed a lesser density as comparison to the samples prepared by Pathak and Pandey (2020) indicating a higher level of porosity in the case of SPS prepared sample which may be the reason for the decrease in mechanical properties. The presence of higher level of porosity in the case of SPSed samples can be also confirmed by the corrosion rate obtained from the potentiodynamic polarization test. The samples prepared by SPS showed a corrosion rate of 0.63 mmpy in Hank’s solution whereas the microwave sintered sample exhibited a corrosion rate of 0.275 mmpy for the Zn–5HAP sample. The indirect cytotoxicity assay involving MC3T3-E1 cells demonstrated grade 2–3 cytotoxicity (viability: 51.99 ± 8.5 at 24 h) in the case of pure Zn. On the other hand, the Zn–xHAP MMCs showed excellent biocompatibility with cell viability >80 % at each time point. The grade 3 cytotoxicity of pure Zn extracts (100 % concentration) was also reported by Tong et al. (2018).

Figure 7:

Effect of Fe addition on (a, b) grain refinement, (c, d) crack growth and stress concentration and (e, f) resistance to dislocation. Reprinted from Li et al. (2023) with permission from Elsevier.

By comparing the in-vitro cytotoxicity behaviour of pure Fe and pure Zn available in the literature, it can be concluded that Zn shows a higher level of cytotoxicity as compared to pure Fe. However, Fe can induce oxidative stress and damage the cellular components due to the formation of reactive oxygen species through the Fenton reaction. The cytotoxicity effect strongly depends on the concentration of ionic species present in the extract. Because Zn has a faster corrosion rate than Fe and the upper intake limit of Zn (40 mg/day) is lower than the upper intake limit of Fe (45 mg/day) (Table 1), the medium contains a larger amount of Zn ions than Fe ions, which is responsible for the increased cytotoxicity in the case of Zn.

5 Powder metallurgy assisted iron and zinc-based bone scaffold preparation

Increasing the surface area of an implant can enhance the corrosion rate and osteogenesis as reported by multiple studies (Alvarez and Nakajima 2009; Barfeie et al. 2015; Hutmacher 2000; Lewis 2013; W. Wang et al. 2017). The surface area of an implant can be increased by incorporating varying levels of porosity through different manufacturing approaches. To this end, two techniques i.e., space holder and rapid prototyping are found to be extensively used to fabricate metallic scaffolds. The space holder technique has the capability of producing highly porous metallic scaffolds having closed and/or interconnected pores with perfect randomness. Pore interconnectivity which is an essential parameter for corrosion can not be fully controlled by the space holder technique. On the other hand, rapid prototyping technique can produce ordered open pores in a scaffold ensuring proper pore connectivity. Mandal et al. (2021) used the spaceholder technique to fabricate a Fe–25Mn–10Cu alloy scaffold with porosity ranging from 42 to 76 %. Higher interconnectivity of pores was observed in the sample having the maximum porosity, which resulted in a high corrosion rate of 2.75 mmpy and 1.56 mmpy evaluated at the end of 30 and 90 day immersion periods respectively. The samples having total porosities of 42 %, 53 % and 62 % also showed a corrosion rate greater than 0.75 mmpy during the 30 day immersion period. However, the UCS and elongation were adversely affected by the increase in porosity. The 76 % porous scaffold exhibited a low UCS of 7.21 MPa with a failure strain of 3.9 %. A high cell proliferation rate of MG-63 cells was observed in the case of all the scaffold samples. Similarly, Huang et al. (2019) fabricated Fe–30Mn scaffolds with open porosity ranging from 5.7 to 13 % by using ammonium bicarbonate as the porogen. The scaffold having 13 % open porosity was determined to have the optimum combination of UCS, Young’s modulus and corrosion rate (evaluated in α-MEM medium) of 381 MPa, 1.29 GPa and 0.98 mmpy respectively. Interestingly, the direct and indirect cytotoxicity testing involving mouse bone marrow stromal cells (BMSC) revealed the cytotoxicity effect of a sample containing 13 % open porosity. The Mn ion release in the case of 13 % open porous sample was found to be higher (7.1 mg/day) than the upper intake level of Mn i.e. 5 mg/day (Huang et al. 2019). Also, the high rate of metal ions and particulate leaching created hinderance in cell proliferation. Similar to iron scaffolds, Zn scaffolds with porosity varying from 11.3 to 63.3 % were fabricated by Yao et al. (2022) by vacuum hot press sintering using NaCl as space holder particles. The compressive yield strength, elastic modulus and corrosion rate determined from weight loss measurement (in revised SBF media) of the scaffolds were in the range of 14.2–73.7 MPa, 1.9–6.7 GPa and 0.41–4.24 mmpy respectively. The cytocompatibility assessment by direct cell seeding (mouse pre-osteoblasts MC3T3-E1) on the scaffold surface showed improved cell adherence and proliferation ability with increase in the porosity. However, the scaffold having 63.3 % porosity reported to have an adverse effect on cell proliferation (Figure 8) which can be due to the high degradation rate (4.24 mmpy) of the scaffold. To address the cytotoxicity issue associated with high porosity, Yao et al. (2023) reinforced the Zn matrix with 1 wt% Mg and 3 vol% β-Tricalcium phosphate (TCP) bio ceramics while maintaining the same manufacturing and testing procedure. Irrespective of a high corrosion rate i.e. 4.28 mmpy shown by Zn–1Mg–3βTCP–P60 (60 vol% NaCl) scaffold, enhanced cell adhesion and cell proliferation was observed which can be seen in Figure 9. The reason for improvement in cell adhesion and proliferation can be attributed to the presence of Mg and Ca ions which are known to be beneficial for bone tissue proliferation.

Figure 8:

Live/dead staining of MC3T3-E1 osteoblasts with culture duration of 1, 3 and 5 days on the surface of bulk Zn (a_i–a_iii) and Zn scaffolds. (b_i–b_iii) 11.3 % porous scaffold, (c_i–c_iii) 18.7 % porous scaffold, (d_i–d_iii) 38.5 % porous scaffold, (e_i–e_iii) 53.1 % porous scaffold and (f_i–f_iii) 63.3 % porous scaffold. D-image: 3D view scanning and F-view: front view of the D-image. Reprinted from Yao et al. (2022) with permission from Elsevier.

Figure 9:

Live/dead staining of MC3T3-E1 osteoblasts with culture duration of 1, 3 and 5 days on the surface of bulk Zn–1Mg–3βTCP, Zn–1Mg–3βTCP–P40 scaffold and Zn–1Mg–3βTCP–P60 scaffold. Reprinted from Yao et al. (2023) with permission from Elsevier.

Although the space holder approach is inexpensive and may achieve different levels of porosity in a sample, it cannot provide effective control of open porosity or porosities of ordered nature. To address this issue, Sharma and Pandey (2018a, 2018b) and Sharma et al. (2020) fabricated topologically ordered porous iron scaffold (TOPIS) by incorporating template-based additive manufacturing and pressureless microwave sintering process. The use of additive manufacturing in designing the sacrificial scaffold provided flexibility in adjusting the open pore sizes and shapes to achieve varying porosity levels. Further, the use of pressureless microwave sintering (no compaction step) induced microporosity in the TOPIS sample which enhanced the corrosion rate of the scaffolds in the SBF medium. The scaffold samples with a porosity range of 45.6–86.9 % had a UCS value of 13–52 MPa, plateau stress of 4–21.5 MPa, and an elastic modulus of 0.2–0.85 GPa, all of which fall within the mechanical property range of cancellous bone. The maximum corrosion rate (2.25 mmpy) was obtained for truncated octahedron-based unit cell scaffolds having 80.97 % porosity (designed macro pore + micropores). The indirect and direct cytotoxicity test performed with mouse fibroblast 3T3 cells showed a significant reduction in cell viability and cell count with an increase in the treatment duration. Further, the sample with the highest porosity and highest degradation rate showed the maximum reduction in cell viability and maximum cell death implying high Fe concentration (>5 μg/ml) may adversely affect cell proliferation. Recently, Tripathi and Pandey (2024) designed Fe–3HAP scaffold having a hollow core which showed a CYS value of 17.62 ± 1.1 MPa and a corrosion rate of 1.68 ± 0.06 mmpy (when tested in SBF). Similarly, Mishra and Pandey (2021) used micro extrusion-based additive manufacturing technique in conjunction with microwave sintering and obtained TOPIS samples of different unit cell shapes and size. The method incorporated by Mishra and Pandey (2021) reduced the processing steps as compared to (Sharma and Pandey 2018a) by eliminating the mould preparation step. However, scaffold preparation utilising direct metal printing requires spherical powders and specialized metal 3D printers such as selective laser sintering and direct energy deposition, making the technique more costly than the space holder approach.

Insights obtained from the literature review on Fe and Zn-based scaffolds can be summarized as follows:

1. The mechanical properties of Fe and Zn-based scaffolds are equivalent to those of cancellous bone.

2. The optimum porosity range in Fe and Zn-based scaffolds is 40–60 %, beyond which both the mechanical properties and cytocompatibility are adversely affected.

3. Bone scaffolds with random porosity can be fabricated by spaceholder method by using compaction and sintering techniques. The process is cheap and a high level of porosity (>70 %) can be obtained with this method.

4. Without the use of any pressure, conventional sintering and microwave sintering can produce Fe and Zn-based scaffolds with both designed macro porosity and random microporosity. However, the precursor powders should be spherical in nature to facilitate pressureless sintering.

6 Clinical use of iron and zinc-based alloys fabricated by powder metallurgy

The pure Fe sample of dimension ϕ 6.5 mm and 2 mm height prepared by tube furnace was implanted into the dorsal region of Wistar rats (Paim et al. 2020). The follow-up study up to 6 months did not show any significant mass loss indicating the in-vivo mass loss rate of pure Fe to be lower than that of the in-vitro mass loss rate. As the sample was prepared through compaction, the porosity level and the pore size present in the implanted cylinder was smaller which explains its very low corrosion rate in vivo. Irrespective of insignificant mass loss of implants, the implant site showed proliferation of connective tissue and no iron accumulation in the tissue and organs. To improve the biodegradability and bioactivity of Fe, Ulum et al. (2014) prepared HAP and TCP-reinforced Fe composite (5 × 2 × 0.5 mm³) using compaction and conventional tube furnace sintering. The implants were placed in flattened bone defects drilled under the radius periosteum membrane of the radial forelegs in the medio proximal area of five male sheep. This study used radiodensity for the qualitative examination of the degradation process. Among all the composite, Fe-5wt% TCP showed the highest decrease in radiodensity value at the end of the 70-day follow up period indicating higher degradation as compared to Fe-5wt% HAP composite and pure Fe. However, the study did not provide a time frame for the complete degradation of the implant in an in-vivo environment. Recently, Dargusch et al. (2021) investigated the in-vivo (rat model) performance of Fe–35Mn and Fe–35Mn–1Ag alloy prepared through conventional sintering. The degradation rate and in-vivo biocompatibility of Fe-based alloys were compared against frequently used WE43 Mg alloy. Interestingly, this study observed gas pocket formation in Fe–35Mn and Fe–35Mn–1Ag alloy for the first time similar to that of WE43. However, the gas pockets dispersed in between the 4–12 week implantation period. The comparison between the in-vivo corrosion rate showed that the degradation rate of all the alloys was found to be maximum during the 4-week implantation period. The Fe–35Mn–1Ag alloy showed a corrosion rate of 0.22 ± 0.017 and 0.14 ± 0.019 mmpy at the end of 4 weeks and 12 weeks respectively which was comparable to the corrosion rate obtained by WE43 i.e. 0.26 ± 0.013 and 0.17 ± 0.014 for 4 and 12 week period respectively in male rats. However, the Fe–35Mn showed a low corrosion rate of 0.06 ± 0.005 at the end of the 12-week implantation period due to the absence of micro-galvanic corrosion. The Fe–35Mn–1Ag alloy did not show any chronic toxicity during the 12-week study period despite the early inflammatory response. Also, macrophage assisted transportation of degradation products away from the implantation site was also confirmed from this study. Mandal et al. (2021) assessed the in-vivo performance of Fe–25Mn–10Cu porous scaffold by implanting it in rabbit femurs and examining the bone growth at 30 and 90 days after sacrificing the rabbits. The µ-CT images taken at 30 and 90 days indicated the presence of irregularly shaped bone tissues and regularly shaped bone tissue (bone remodelling) respectively around the bone-implant interface. The scaffold with the highest porosity (76 %) demonstrated remarkable bone regeneration both within and outside of the scaffold. The histological analysis, depicted in Figure 10A, showed the presence of Haversian canals, osteoblasts and osteoclasts in abundance at the 30-day implantation period. At the 90-day implantation period, an enhanced proliferation of osseous structure was observed for all the samples. The samples with 62 % and 76 % porosity exhibited more osteoblast and osteoclast infiltration suggesting high level of bone regeneration which can be seen from Figure 10B.

Figure 10:

Histological H&E staining and fluorescence micrograph of implanted Fe-Mn-Cu scaffolds: (A) Histological H&E staining of implanted samples (a–e) at 30 days and (f–j) at 90 days (a: Haversian canal, b: osteoblasts, c: osteoclasts). (B) Fluorescence micrograph of the bone-implant interface (a–e) at 30 days and (f–j) at 90 days (red arrow: new bone, blue arrow: old bone). Reprinted from Mandal et al. (2021) with permission from Royal Society of Chemistry.

The in-vivo investigations on Zn-based systems manufactured using PM methods are limited in the literature. The authors can find only one study reported by Yang et al. (2018) which incorporated pure Zn and Zn–5HAP composite fabricated through the SPS technique in a rat femur condyle model. Pure Zn and Zn–5HAP cylinders of dimension (ϕ2 mm × 5 mm) were implanted into the left or right femur condyle of rats and the condyles were examined by micro-CT and histomorphometric analysis at 4 or 8 weeks. The Zn–5HAP exhibited rougher surface morphology with a decrease in the volume of the implant of 3.2 ± 0.56 % at the end of 8 weeks which was higher than the decrease in volume of the implant in the case of pure Zn (1.7 ± 1.02 %). Although there was no significant difference in the degradation volume of both the material, the Zn–5HAP showed a localized form of corrosion whereas pure Zn exhibited uniform corrosion mode. At week 8, the Zn–5HAP composite had a stronger effect on stimulating new bone production by replacement of fibrous layer by new bone tissue which can be seen from the Van Gieson staining of hard tissue sections given in Figure 11.

Figure 11:

Histological staining (Van Gieson) of hard tissue sections at weeks 4 and 8 for (a) pure Zn and (b) Zn–5HAP composite. Red rectangles: magnified bone-implant interface, red triangle: newly formed bone. Reprinted from Yang et al. (2018) with permission from Elsevier.

By comparing the in-vitro and in-vivo corrosion rates of Fe and Zn-based implants, it can be inferred that the in-vivo degradation rate is always lower than the in-vitro corrosion rate. This observation is supported by multiple studies (Dargusch et al. 2021; Kiær et al. 1992; Kraus et al. 2014; Ulum et al. 2014; Yang et al. 2018). The reason for such behaviour can be ascribed to limited oxygen availability in the surrounding tissue of implants (in vivo) which inhibits the cathodic oxygen reduction reaction. Hence, the mass transport of dissolved oxygen to the metal surface becomes the rate-determining step in the in-vivo condition.

7 Outlook and conclusion

With careful adjustment of the degradation behaviour and improvement in bioactivity, Fe and Zn-based bioimplants can be a superior option to Mg-based bioimplants. The addition of nobler elements to the Fe and Zn matrix enhances the overall corrosion rate by accelerating galvanic corrosion. Elements like Ag, C, Mn, and Pd have been known to enhance the corrosion kinetics in Fe-containing systems whereas elements like Mn, and Fe have been reported to increase the corrosion rate in Zn-containing systems. The biocompatibility and corrosion rate are concurrently improved by adding bioceramics like HAP and bioglass to the Fe and Zn matrix. However, the volume fraction of the second phase should be optimized to achieve desirable mechanical, electrochemical, and biological performance. The benefits of PM approaches, such as porosity control and manufacturing of complicated geometry to enhance the corroding surface area, can be used to improve the deterioration rate of Fe and Zn-based bioimplants. Although research on the fabrication of Fe and Zn-based bioimplants by PM route increased significantly in the last decade, certain issues have to be addressed to facilitate their medical use which is summarized below.

1. More long-term in-vivo investigations on Fe and Zn-based PM implants are needed to completely understand their biodegradability and biocompatibility nature. Specifically, the effect of constituent element ions on tissue growth must be addressed and the safe dosage of constituent element ions should be identified.

2. The role of dissolved oxygen in the in-vitro testing media on the corrosion rate of the Fe and Zn-based implant should be considered to minimize the mismatch between the in-vivo and in-vitro corrosion rate.

3. Perfusion bioreactor can be used to perform in-vitro studies to closely mimic the dynamic in-vivo environment.

4. Time-dependent decrease in the mechanical properties and fracture modes of Fe and Zn-based load bearing implants in in-vitro tests must be explored to eliminate the possibility of premature implant failure.

5. The adverse effect of the high rate of corrosion on cell proliferation of highly porous (>60 %) Fe and Zn-based scaffolds can be mitigated by providing bioactive reinforcement in the scaffold matrix or bioactive coatings over the scaffold surface.

6. The effective surface area that is in direct contact with the corrosion medium can be optimized to adjust the corrosion rate in the initial period of implantation. Additive manufacturing combined with the PM route can be used for this purpose.