**6. Immunogenic Effects on the Biodegradation Behaviour of Scaffolds**

Immunogenicity is a biological response to the presence of non-compatible foreign substances or living organisms in the body. This reaction can cause complications for one's health. Therefore, biocompatible scaffolds are imperative to circumvent immunogenic effects. The by-products of degradation, such as monomers, oligomers, and polymer fragments, should be biocompatible with the human body, and should be able to pass through filtering organs without causing any complications. Scaffold materials with a low degradation rate might lead to transplant failure, due to negative immune responses. Woodard and Grunlan (2018) [75] underlined the scaffold's dimensions as a factor that influences degradation. This idea was also presented in another study [74].

Figure 12 illustrates how different biodegradation rate trends are capable of tuning the immunogenicity of scaffolds. A poor degradation rate of a non-compatible scaffold will inhibit tissue regeneration, since the scaffold will continuously trigger immune reactions. However, incompatible scaffolds with high degradation rates could compromise tissue regeneration rates, due to the absence of cellular support. Altering the material degradation rate seems to be a promising means of optimising the scaffold's biocompatibility. Natural polymers often exhibit better biocompatibility and biodegradability. However, the degradation of synthetic polymers can be tailored accordingly. Acidic by-products, which are hydrolytically produced from polyester scaffold degradation, may also cause physiological inflammatory responses [75]. In some cases, a low pH environment can unnecessarily accelerate the scission of scaffolds. Therefore, biodegradable polyester for physiological purposes can be optimised by introducing basic salts into the polyester, such as calcium carbonate, sodium bicarbonate, and calcium hydroxyapatite [75]. The use of biodegradable natural polymers, such as collagen, was suggested, according to the presence of collagenase as a physiological enzyme [90]. The presence of natural polymers in scaffolds only triggers mild biological responses, and this can prevent severe immunogenicity side effects.

**Figure 12.** Illustration of the different immunogenic responses towards the specific biodegradation trends of scaffolds.

#### **7. Common Conductive and Biodegradable Scaffolds**

*7.1. PEDOT-Based Scaffolds*

#### 7.1.1. Characteristics of PEDOT-Based Scaffolds

To utilize CPs for developing and synthesizing scaffolds with properties that are tailored for use in tissue engineering, the suitable conductive and hybrid systems of biocompatible scaffolds must be discussed. Extensive research is ongoing to optimise the stability of scaffolds, by incorporating composite materials to overcome the problems with tissues [18,38,58,68,91]. The scaffold materials must fulfil the criteria of convenient sterilisation, biocompatibility, and non-toxicity [92]. The seamless electrical communication among cells, and the optimised growth of cells, can be achieved by exploiting scaffolds with sufficient electrical conductivity. Recently, the focus of scaffold-based TE is on the enhancement of bone healing via electrical stimuli with CPs [40]. The addition of modified electroactive oligomers can control the biodegradability of CPs. These grafted copolymers are connected via degradable ester linkages, and are highly sought after in biomedical applications that employ pyrrole, aniline, or thiophene groups [23]. Unfortunately, electroactive aniline-based oligomers are toxic to human bodies. In response to this observation, Mawad et al. (2016) proposed 3,4-ethylene dioxythiophene (EDOT)-based oligomers as an alternative to replace aniline-based oligomers, to minimise the biomaterial's toxicity [54].

PEDOT can be chemically tuned to alter the mechanical and electrical properties of scaffolds. This tuning can promote the covalent attachment between biomolecules and scaffolds to become biocompatible [93]. In addition, conductive scaffolds are conductive for the differentiation and proliferation of electrically stimulated responsive cells [28]. PEDOT: PSS is a common biocompatible CP behind conductive scaffolds. Figure 13 shows the chemical structure of PEDOT: PSS. This copolymer has a moderate band gap and excellent stability [25]. For example, the addition of PEDOT: PSS in a chitosan-based electrospun scaffold not only enhances the scaffold's mechanical and electrical conductivity, but also improves its biocompatibility and cell viability [24]. The findings regarding the biodegradability of various scaffolds including conductive scaffolds from previous research are summarised in Table 3. Predominant crosslinking in scaffold fabrication (as discussed in the Crosslinking Process section in Fabricating Conductive-Polymeric Scaffolds (Section 3)), increases the mechanical properties and stability of the scaffold at the possible expense of the scaffold's biodegradability.

**Figure 13.** The chemical structure of PEDOT: PSS with the presence of sulfonate ions from an oxidant [94].
