Electrochemical Etching

The most extensively studied membrane-producing electrochemical etching method is the anodic membrane technique. The membranes fabricated with this technique produce a honeycomb-like and ordered structure. The pore morphology and size can be controlled through the process of anodization [117]. The organization of the porous structure depends on the voltage and chemicals used in the fabrication. These ordered channel assemblies of membranes are obtained by an anodization process. The most effective technique for preparing well-arranged porous membranes with large dimensions involves this process. During the anodization procedure, thin ordered structures are engraved within a larger dimension membrane [118]. Within the small ordered structures biomolecules are encapsulated, and these membranes are used for diffusion-controlled delivery systems. The drug molecules are encapsulated inside the micelles as biocapsules and it has been shown that membranes containing biocapsulesare able to release the drugs in a controlled fashion [119].

## 5.1.4. Surface Modifications

When membranes come into contact with physiological fluids, three main processes occur which create problems, namely, biofouling, degradation of the membrane, and immune reactions caused by the membrane. There are various approaches to addressing these problems, and these are discussed as follows. If cells, proteins, and other materials accumulate on a membrane surface when the membrane is in contact with a biological environment, a process is occurring which is called biofouling [106,120]. The second issue is that this also causes tissue encapsulation, which leads to fibroblast proliferation, collagen synthesis, and proliferation of blood vessels. These processes in turn lead to vascular tissue capsule formation, which delay the transport of glucose molecules in biological environments due to steric hindrance [121]. Wound healing occurs via the processes of hemostasis, inflammation, and formation of scars and repair. During the implantation of the membrane, cells of epithelial connective

tissue and the basement membrane may be damaged. Firstly, the bruised area is filled with coagulated blood, and this clotting allows neutrophils. The day after wound injury, the inflammatory cells disturb the function of the membrane by taking nutrients and releasing proteolytic enzymes and free radicals. On the third day, there is occurrence of macrophages and granulation tissue in the wounded area, followed by neovascularization on fifth day. Finally, at the end of the first month, the formation of a mature scar in the epithelial layer of the tissues is observed. Hence, the biocompatibility depends on the surface of the implanted membrane, which influences each stage of the process. A thick vascular fibrous scar formation leads to di ffusion of analytes and uptake of nutrients, resulting in reduced response of the membrane [115,122].

In order to reduce biofouling, several reports have demonstrated the use of coatings and other methods of surface treatment. For this, the membrane surface is treated with cross-linked polymers of poly (hydroxyethyl methacrylate) or poly (ethylene glycol). Polymer coatings on the membrane surface result in electrically neutral, polar, flexible, and swellable membranes in water, and create an interface between the membrane surface and the physiological environment. Coatings of poly (hydroxyethyl methacrylate) or poly (ethylene glycol) are considered the most attractive for membranes because water-soluble drugs diffuse through the water-swollen polymer layer [123–125].Biocompatibility of the implantable membrane is characterized by inflammatory responses. Surfactants are also called surface-active agents and have hydrocarbon tails attached to polar head groups. Many membranes used for drug delivery contain these surfactant molecules as a plasticizing agent. Unexpectedly, these surfactants diffuse out of the membranes and to the surface, until they ge<sup>t</sup> depleted. Accordingly, these agents need calcium chelating plasticizers which limit the enzyme in the coagulation cascade [126,127]. Keeping in mind the characteristics of the membrane and the physiological environment, the biocompatibility of the material should also be addressed. In addition, it is very essential to prove that there is very little or no leaching, degradation, biofouling, and inflammatory responses. Therefore, selection of the perfect surface coating is important to figure out problems in a biological environment [128].

### *5.2. Drug Delivery by Membranes*

The use of membranes to deliver drugs/bioactives is opening up new therapeutic advantages like increasing the solubility of bioactives, protecting bioactive molecules from degradation, providing a sustained release of the actives, improving drug bioavailability, providing targeted delivery, decreasing lethal e ffects, o ffering an appropriate form for all routes of administration, and allowing for rapid formulation development. Moreover, they can carry one or more bioactive agents and have been developed into di fferent classes of carriers. The di fferent carriers can be carbon-based nanomaterials, polymeric membranes, and inorganic membranes [129].
