Innovative technologies on the fabrication of 3D/4D smart hydrogels and its biomedical applications - A compendious review

Exploring cutting-edge ways to enhance healthcare for the sick and elderly persists worldwide. Sustainable processes and innovative green systems are a substantial necessity for evaluating and remedying the causes of health deterioration. Tissue engineering and genetic engineering have steadily developed into potential methods to address the future demands of patients. The three-dimensional cell, which can anticipate the efficacy of the pharmaceutical ingredients or its toxicity strata, may genetically be manipulated to understand the disease processes or to screen small molecule therapies. In this outlook, 3D strategy promises to be much more plausible than the prevalent two-dimensional techniques [[1], [2], [3]].

In the spectrum of 3D networks, hydrogels are the hydrophilic networks of water-swollen macromolecule polymers. Their cross-linking is either chemical or physical. They are liquid from 4 °C to room temperature but mutate to gel form when incubated at about 36 °C. It is a self-explanatory depiction of its physical condition and compositor attribute. The 3D bulged or standard forms provide a significant surface area and may thus be utilized to immobilize a colossal proportion of materials [3] Being hydrophilic 3D networks, they can absorb a vast amount of water or biological fluids with sheer biocompatibility; thus, they an ideal candidate for biosensors [4], drug delivery vectors [5], and transporters or matrices for cells in the field of tissue engineering [6], etc.

Beyond the biomedical applications, hydrophilic 3D hydrogel networks have found usage in several other fields leveraging hydrophilic porous structures, such as in eco-remediation, where hydrophilic absorbent properties have been used to develop hydrogel-based absorbents for oil and chemical spill clean-ups, which is a massive threat to marine life. The crosslinked polymers can soak up aqueous solutions and hydrophobic oils upon emulsion formation and functionalization. Water treatment would be a conjugated application [7,8]. Hydrogel beads and membranes are also being designed to remove heavy metals, dyes, and toxins from wastewater through absorption succeeded by easy separation. The charged surfaces aid in ionic interactions [9,10]. Stimuli-responsive hydrogels that swell or de-swell in response to temperature, pH, or biomolecular interactions serve as optical, electrical, or mechanical signal transducers for self-sensing actuator applications [11,12]. They can be used as a coating on optical fibers, microcantilevers, or test strips to translate the volume changes into measurable optical or deflection signals [13]. The tunable porosity has enabled the use of hydrogel membranes for size-selective separation of exosomes, proteins, DNA, etc., in an aqueous system [14]. The matrices can selectively allow the passage of small molecules while retaining bigger moieties. Incorporation of metallic nanoparticles or catalyst particles within hydrogel networks to enable their use as heterogeneous catalysts for supercapacitors [15], water splitting [16], and organic syntheses [17] with easy retrieval and recycling of the polymeric catalyst.

Printable materials for biomedical applications, such as tissue repair and regeneration, drug delivery, biosensing, and cell culturing, are emerging strategies in biomedical research. They must have good printability, mechanical strength, robust interfacial strength, and desired biocompatibility. Though obtaining suitable printable biomaterials remains difficult, hydrogels have been one of the most significant materials of interest to biomaterial scientists for many years [[18], [19], [20], [21], [22], [23]]. Wichterle and Lim were the first to report on them (1960), where their work focused on HEMA hydrogels [24]. Hydrogels pose versatile biomedical attributes such as antibacterial, adherence, hemostasis, anti-inflammatory, anti-oxidation, material administration, self-healing, sensory, conductance, and newly developed incision surveillance [24]. They are the first biomaterials intended for use in the human body. By combining the hydrogel predecessor solution with the cell solution, cells can be embedded into the voids of hydrogels. The resulting mixture is then dispensed in a vessel that can promote cell culture. The cells will be encapsulated inside the gel during gelation, and hydrogel can act as an external cellar matrix for assays. The cells processed inside a 3D hydrogel have a relatively higher original characteristic and reproducibility than those cultured in a 2D culture. Hence, with their non-destructive and promotive character, hydrogels play a phenomenal role in developing modern bio-medical research and the medicinal world [3].

AM provides high automation, repeatability, and exact control over distinct components' incision points in a 3D model. Hence, AM makes it particularly appealing for synthesizing hydrogels for diverse and precise biological applications [25]. Printable and biocompatible hydrogels provide favorable bio-mimetic environments for active cells, such as elevated water content, perforated structure, incorporation of bioactive molecules, and tenable mechanical properties and degradation rates [26] [27] [28]. Yet, most typical hydrogel polymers are stiff, fragile, and mechanically weak, making them unsuitable for handling and soft/ elastic tissue applications. As a result, developing printable, high-strength, and elastic hydrogel materials for 3D printing in tissue repair and regeneration is vital, challenging, and exciting. A substantial scope in regenerative medicinal strategies has been devised to regenerate organs like skin, spinal cord, cartilage, bone, etc. The future is engraved in the regeneration of complex organs or systems, such as kidneys, liver, mature stem cells, bone marrow, and more [[29], [30], [31], [32]]. The simple chemical design and functionalization (Fig. 1) have employed hydrogels in precise 3D printing of scaffolds. Researchers are interested in hydrogels that include naturally occurring macromolecules, by which they can quickly reproduce biological tissues with collagen-like features [33].

Nanomedicine can be designed to attack and kill specific microbes or even malignant tumors and has paved the way for targeted drug delivery(TDD). TDD has been reducing the quantity of medication necessary for therapeutic efficacy. Hydrogel-based TDD is now prevalent to improve established therapy procedures, such as autologous chondrocyte implantation (ACI) and matrix-induced autologous chondrocyte implantation (MACI) micro-fracture surgery for ailments like cartilage defect healing [1,2].

Regeneration is an imperishable biomedical research arena. Permeability, multilayer form, desirable dimensions, interconnectivity, and mono- or multi-material fabrication are the vital properties of hydrogels in diverse regeneration strategies. AM components comprise scaffolds for complex tissue regeneration and wound treatments. They include fibers that exactly imitate soft tissue, have identical oxygen/nutritional components or metabolite diffusion, and provide nanoscopic frameworks for cutaneous medicine. These structures [highly bio-compatible and negligibly toxic polyethylene glycol (PEG)] might be filled with medications and biological indicators for speedy wound care, effective surgical treatments, etc. [36]. This comprehensive review aims to elucidate numerous additive manufacturing techniques to synthesize hydrogels like extrusion, inkjet, SLA, and DLP. The study emphasizes the biomedical applications of additively manufactured hydrogels in targeted drug delivery, wound healing, bio-printing, and tissue regeneration of the spinal cord, skin, cartilage, and nerves. The limitations and prospects of AM-hydrogels in such applications have been critically elucidated at the tail of the paper.

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