1 Introduction

Hydrogels are matrices formed by the physical or chemical cross-linking of soluble polymers, essentially hydrophilic macromolecular structures. Due to their high sensitivity to the physiological environment, soft-tissue-like water content, and adequate flexibility, hydrogels are excellent candidates for biomedical applications [1, 2]. Being porous, they allow for the absorption of wound exudates and the passage of gases [3, 4].

Hydrogels can be classified under multiple categories. They may be categorized based on source (natural or synthetic), polymeric composition (homopolymeric, copolymeric, or multipolymer interpenetrating polymer), configuration (amorphous, semi-crystalline, or crystalline), type of cross-linkages (physical or chemical), physical appearance (matrix, film, or microsphere), and inherent electric charge (ionic, nonionic, amphoteric electrolyte, or zwitterionic) [5, 6]. However, the most widely accepted mode of classification is based on the source. The large-scale synthesis of chemically synthesized biopolymers is cost-intensive. It leads to the release of multiple unwanted chemicals into the environment, thereby impacting the environment and human life alike [7].

Nanocomposite hydrogels (nanomaterial-loaded, hydrated polymeric networks with better elasticity and strength than conventional hydrogels) have enormous potential for biomedical applications [8]. The core aim of integrating nanoparticles into hydrogels is to augment the thermal and mechanical stability, along with water vapor transmission and swelling capacity, of the resultant membranes, especially in stress areas [1]. Nanoparticles have several unique attributes due to their size and surface area [9]. Nanomaterials possess significant potential in various fields based solely on their nanoscale size, diverse structures, and environmental friendliness. Numerous studies have shown that nanoparticles perform well in biomedicine due to their good biocompatibility and excellent mechanical, thermal, and optical properties [10]. Inorganic nanoparticles that have been used for biomedical applications include metal oxides (e.g., TiO2), clays (e.g., bentonite), AgNO3 nanoparticles, hydroxyapatite (HAP), etc. However, these do not possess biodegradable properties, making their usage superficial [1]. Gaping wounds (such as those caused by major accidents) require better aid with biodegradable properties. Nanocomposite hydrogels formulated by green synthesis methods are biodegradable and, hence, have numerous biomedical applications. Nanocomposite hydrogels (NH) have become progressively significant with widespread applications in various areas such as controlled drug delivery systems (CDDS), humidity sensors, artificial implants, and artificial skin development [4]. Nanohydrogel development integrates natural and synthetic nanomaterials, including carbon-based nanomaterials like carbon nanotubes (CNTs), graphene, and nanodiamonds. Polymeric nanoparticles, such as dendrimers and hyper-branched polymers, contribute to structural diversity. Inorganic and ceramic nanoparticles like hydroxyapatite, silicates, and calcium phosphate provide bioactivity and compatibility. Metal and metal oxide nanoparticles, including gold, silver, and iron oxides, offer unique properties such as antibacterial effects and magnetic responsiveness, enhancing the versatility of nanohydrogels for various applications [11]. All the materials used for nanohydrogel are detailed in Fig. 1.

Fig. 1
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Nanocomposite hydrogels combine various nanoparticles with polymers, crosslinked chemically or mechanically, allowing customizable physical, chemical, and biological properties [1, 11, 12, 14]

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There is still a gap in summarizing the latest breakthroughs in their biomedical and biotechnological applications. This manuscript aims to bridge this gap by reviewing the recent advancements in nanocomposite hydrogels with tailored functionalities and providing a comprehensive overview of various types of nanocomposite hydrogels and their expanding biomedical applications. We believe that this review will inspire researchers in this field by providing valuable insights and ideas on harnessing the potential of these versatile nanocomposite hydrogels.

2 Classification of hydrogel based on the type of cross-link junctions

Hydrogel classification usually depends on factors such as their swelling ability, ionic strength, method of synthesis, and the nature of cross-linking agents [12]. Based on their nature of cross-linking, hydrogels are classified into two types—Physical Hydrogel and Chemical Hydrogel as detailed in Fig. 2.

Fig. 2
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Classification of hydrogels [11, 13]

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2.1 Physical hydrogel

Physical hydrogel is usually formed by weak interactions, such as Van der Waals forces, hydrogen bonding, and electrostatic interactions between polymer reactive groups in an aqueous medium under mild conditions. Physical hydrogels are also known as pseudo-gel/supramolecular particles [13]. Physically cross-linked hydrogels are further classified as strongly or weakly crosslinked. The main difference between the strongly physically crosslinked hydrogels and weakly physically crosslinked hydrogels is that the former have stronger formation of junctions between the polymers, while the latter have temporary junction formation between the polymers which justifies their limited life span. Physically crosslinked hydrogels are found to be useful for various biotechnological and biomedical applications since their polymerization process is carried out without the presence of any organic crosslinking agents [14].

2.2 Chemical hydrogel

Chemical hydrogels involve chemical covalent cross-linking in the formation of polymer chains which makes them highly stable. The bonds can be initiated between polymer chains if the reacting polymer chain consists of functional side groups such as OH, COOH, or NH2 in their structure. Chemical hydrogels have good mechanical properties and longer degradation times [12, 14].

2.3 Hydrogel based on ionic interaction

This type of cross-linking is based on the presence of ions to form internal networks that lead to the formation of hydrogels. Hydrogels, formed from such cross-linking have great adhesion strength and are easily extensible [15]. A known example of such hydrogels is Alginate which is used as a template for encapsulation of living cells and release of proteins. Alginate is cross-linked with calcium ions through ionic interactions [12].

2.4 Enzyme-based cross-linking hydrogel

This type of cross-linking is based on the use of enzymes as reactants that help in reducing the overall toxicity caused by chemical reagents. The hydrogels formed due to the presence of enzymes that act as additives lead to the generation of new bonds between the polymer chains [15]. Tyrosinase, a well-known oxidizing enzyme found in plants and animal tissues has been used to prepare a hydrogel by cross-linking gelatin with chitosan [12].

2.5 Photosensitive functional group-based cross-linked hydrogels

This type of hydrogel formation is based on photoresponsive polymers. UV or visible light's direct contact usually causes damage in the tissues and, they cannot penetrate deep into the tissues. Therefore, certain biomaterials consisting of chromophore groups are used to develop nanosystems, so that they can absorb light in the near-infrared (NIR) range. The NIR light is chosen to be the best option for developing photosensitive hydrogels as they possess properties such as good penetration through the skin and other tissues [13].

2.6 Supramolecular cross-linking

Supramolecular hydrogels are formed through host–guest interactions and other reversible bonds, providing dynamic and adaptable properties [16]. Fang et al. designed a self-healing supramolecular hydrogel using cyclodextrin-based host–guest interactions [17]. This hydrogel can repair itself after mechanical damage, making it ideal for applications requiring long-term stability and resilience.

2.7 Dual and multiple cross-linking

Combining multiple cross-linking mechanisms results in hydrogels with synergistic properties. Zhang et al. developed a dual cross-linked hydrogel using both ionic and covalent bonds, achieving a balance between robustness and flexibility. This dual cross-linked hydrogel is particularly useful for cartilage repair, addressing the need for materials that can withstand physiological stresses while supporting tissue regeneration [18]. The recent advancements in hydrogel cross-linking have led to innovative applications across various biomedical fields. By focusing on novel cross-linking strategies, these studies not only classify hydrogels but also highlight their potential for significant therapeutic and regenerative.

3 Classification of interpenetrating network hydrogels

Interpenetrating network (IPN) hydrogels are composed of two or more polymer networks that are physically entangled but not covalently bonded to each other [19]. This unique structure imparts enhanced mechanical properties and functionality. Recent research has focused on novel applications and innovations within this classification, demonstrating significant potential in various biomedical fields.

3.1 Homopolymeric hydrogels

Homopolymeric hydrogels arise from a singular monomer species, with the specific composition determined by the polymer's inherent characteristics and the method of polymerization employed [20]. Cross-linked homopolymer hydrogels are found to be utility in drug delivery systems and as materials in contact lenses. Notable polymers, including Polyethylene Glycol (PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), and polyacrylic acid (PAA), are commonly employed in the synthesis of homopolymeric hydrogels [12]. The detailed classification of hydrogels is shown in Fig. 1

3.2 Copolymeric hydrogels

Copolymeric hydrogels are composed of two or more distinct monomers, with at least one of these monomers possessing a hydrophilic character [21]. Copolymeric hydrogel networks are often non-water soluble [22]. Poly (vinylpyrrolidone/acrylic acid) poly (acrylamide-co-acrylic acid) and poly (lactic acid)-poly (ethylene glycol) (PLA-PEG) are some examples of copolymeric hydrogels [21].

3.3 Semi‐interpenetrating hydrogels

Semi-interpenetrating (SIP) hydrogels are created by incorporating natural amino acid-derived polymers, such as PACG (poly (N‐acryloyl 2‐glycine), into a PVA matrix with physical crosslinking [23]. SIP hydrogels have a wide range of applications, including in drug delivery systems, wound dressings, tissue engineering, and responsive materials, making them an area of significant interest in the field of biomaterials and polymer science [24].

3.4 Interpenetrating hydrogels

Over the past few decades, Interpenetrating Polymer Networks (IPN) hydrogels have garnered significant interest, primarily driven by their widespread use in the biomedical field. IPNs can be likened to "alloys" of cross-linked polymers, where at least one is created or cross-linked close to the other, without forming covalent bonds between them. These networks remain inseparable unless chemical bonds are intentionally broken [25].

3.5 Sequential interpenetrating networks

Sequential IPNs are formed by sequentially polymerizing different networks within each other. A novel study by Lanzalaco et al. established a sequential IPN hydrogel using chitosan and poly(N-isopropylacrylamide) (PNIPAM), aimed at drug delivery [26]. This hydrogel exhibited dual-responsive behavior, responding to both temperature and pH changes, allowing for precise control over drug release rates. The sequential IPN structure provided a versatile platform for tailored drug delivery systems [26, 27].

3.6 Gradient interpenetrating networks

Gradient interpenetrating network (IPN) hydrogels, characterized by their entangled polymer networks with gradient properties, have shown significant promise in recent biomedical research [28]. A novel approach by Bousalis et al. developed a gradient IPN hydrogel for use in nerve regeneration. This hydrogel exhibited a gradient of stiffness, mimicking the natural gradient found in neural tissues, and supported the directional growth of nerve cells. The innovative gradient design enhanced cell alignment and connectivity, crucial for effective nerve regeneration [28]. Further advancements include a bioinspired multifunctional gradient hydrogel designed for soft robotics. This hydrogel exhibits ultrafast actuation and high sensitivity due to its gradient structure, enhancing its responsiveness to external stimuli [29]. Additionally, graphene/polyacrylamide IPN hydrogels have been employed for wastewater treatment, utilizing their gradient properties for efficient molecular separation and environmental remediation [29].

3.7 Double network hydrogels

Double Network (DN) hydrogels are characterized by their remarkable mechanical properties, which are achieved through the integration of two distinct polymer networks [30]. The Current innovations have focused on enhancing their applications in biomedical fields, particularly for wound healing and tissue engineering. A study by Zhao et al. developed an antibacterial and antioxidant electroactive injectable hydrogel with self-healing properties, ideal for cutaneous wound healing due to its hemostasis and adhesiveness [31]. Another study by Guo et al. and Carpa et al. introduced a conductive, injectable composite hydrogel inspired by mussel adhesion, which promotes skin regeneration by providing antibacterial and antioxidant effects [32, 33]. Additionally, Guo et al. created a self-healing adhesive chitosan hydrogel that exhibits antioxidative, antibacterial, and hemostatic activities, thus accelerating skin wound healing [32]. This innovation highlights the ongoing efforts to improve the functional properties of DN hydrogels for more effective and versatile biomedical applications. These current developments underscore the potential of DN hydrogels in creating more strong and multifunctional materials for various medical applications, paving the way for future innovations in the field.

4 Classification based on source

Based on this most widely followed classification, hydrogels are divided into- Natural hydrogel and Synthetic hydrogel. This categorization holds significance due to its influence on stem cell differentiation and proliferation, as the chemical composition of the substrate plays a pivotal role in these processes. Both natural and synthetic hydrogels have found extensive application in the regulation of stem cells [34, 35].

4.1 Natural hydrogel

Naturally derived polymers typically possess relatively low mechanical strength limiting their utilization in biomedical fields. Chitosan, Dextran, and Alginate are examples of natural hydrogels [34, 35].

4.2 Synthetic hydrogel

In contrast, synthetic polymers are favored for addressing this limitation, as they offer advantages such as ease of synthesis, cost-effectiveness, and the ability to tailor their properties to specific applications, making them increasingly valuable in various biomedical applications [34, 35].

5 Applications of nanoparticle-loaded hydrogels

Nanoparticle-loaded hydrogels are a significant innovation in biomedical applications. They offer unique properties and versatile functionalities, enhancing performance in wound healing, drug delivery, and tissue engineering [33]. Silver-loaded hydrogels provide antibacterial properties and improve wound healing [36, 37]. Gold-loaded hydrogels enhance drug stability and delivery [38]. Silica-loaded hydrogels increase mechanical strength and control drug release [39]. These hydrogels represent transformative solutions, requiring continuous research to optimize and expand their applications are presented in Table 1.

Table 1 Comparison of different hydrogels and applications
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6 Biomedical applications of various hydrogels

Hydrogels have become integral in biomedical applications due to their versatile properties and functionalities. These materials can be adapted to exhibit specific characteristics, making them suitable for diverse applications, from drug delivery to tissue engineering. Table 2 shows the comparative analysis of various hydrogels, summarizing their properties, in vitro and in vivo applications, and recent findings. Thermo-responsive Hydrogels, studied by Zhang et al. transition at physiological temperatures, making them suitable for 3D cell culture and drug delivery [48]. Hybrid Hydrogels, researched by Cai et al. and Rana et al. combine properties of different materials, making them ideal for anticancer drug delivery and wound healing [49, 50]. Chitosan-based Hydrogels, explored by Taokaew et al. are biocompatible and used for controlled drug delivery [51] Supramolecular Hydrogels, also studied by Zhang et al. and Taokaew et al. are reversible and responsive, making them ideal for smart drug delivery systems [48, 51]. Poly (ethylene glycol) Hydrogels, studied by Sun et al. are biocompatible and commonly used in drug delivery systems [52]. Gelatin-based Hydrogels, researched by Bupphathong et al. support cell adhesion, making them beneficial for cardiac tissue engineering [53]. Lastly, Cellulose-Chitosan Hydrogels, studied by Alven et al. are effective radical scavengers, making them suitable for wound healing [54].

Table 2 Summary and biomedical applications of various hydrogels, both in vitro and in vivo
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7 Nanocomposite hydrogels in advanced biomedical

Nanocomposite hydrogels are revolutionizing medicine with applications in targeted drug delivery, tissue engineering, wound healing, biosensing, and cancer therapy. Their biocompatibility, responsiveness to stimuli, and ability to mimic natural tissues make them ideal for diverse therapeutic uses, including regenerative medicine, artificial skin, tissue engineering, artificial bones, dental application, and biorobotics, enhancing patient outcomes and transforming healthcare solutions [7, 8, 10, 12, 13].

8 Nanotheranostics: NHs for therapeutic use (drug delivery and diagnosis)

Nanotheranostics, defined as an integrated combination of target-specific diagnostics and delivery of therapeutics based on nanotechnology platforms has emerged as a paradigm shift in addressing current treatment roadblocks and persistent clinical needs [55]. Rossi et al. reported the development of chitosan ascorbate nanoparticles for the vaginal delivery of antibiotic drugs in atrophic vaginitis [56]. Naeem et al. reported the synthesis of novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels for in vitro drug release of model drug Mannitol [4]. Farhadnejad et al. reported the formulation of a new drug carrier by a combination of montmorillonite (Mt) and a pH-sensitive polymer, carboxymethyl cellulose (CMC), which was able to release propranolol hydrochloride (PPN) sustainably, in the stimulated gastrointestinal conditions. The novel Mt/CMC NH beads were prepared successfully by dispersion of Mt-PPN nanohybrids in the CMC matrix following cross-linking using Fe3+ ions. PPN is a beta-blocker medication used to treat tremors, angina, hypertension, cardiac rhythm problems, and other heart or circulation issues [57].

Insulin injection is known as a sure cure for diabetes mellitus (a disorder caused by decreased production of insulin or by reduced ability to use insulin, leading to a glucose level increase in the blood). However, subcutaneous insulin injections have been reported for patient noncompliance, discomfort, local infection, and pain. Therefore, nano-sized drug delivery mechanisms have gained popularity in the oral delivery of insulin for diabetes treatment [58]. Jafari et al. reported the manufacturing of a polymeric hydrogel for drug delivery of insulin. They synthesized poly N-isopropyl acrylamide (NIPAAm)-Methacrylic acid (MAA)-Hydroxy ethyl methacrylate (HEM) copolymers by radical chain reaction in 1,4-Dioxane under N2 gas conditions and encapsulated insulin within them by modified double emulsion method and the in vitro release study were conducted in two different pH (pH 2.0 and 7.4 to simulate stomach and intestine conditions). The results showed a pH-controlled release behavior by the NH with 80% and 20% release at pH 2.0 and 7.4 respectively [59]. Karnoosh-Yamchi et al. reported formulation of pH-sensitive NH from N-isopropyl polyacrylamide, Metaacrylic acid, and Hydroxyethyl methacrylate in 1,4 Dioxane solvent without the addition of any cross-linker, that could be the loaded with human pure insulin by modified dubbed emulsion and gavaged it for diabetic rats. The blood sugar level was found to be much lower in rats fed with NH loaded with insulin in comparison to those administered with direct insulin dose [60].

Renal fibrosis is a result of many chronic kidney diseases, independent of the underlying etiology. Shear-thinning injectable hyaluronic acid-based NHs were reported for use in a mouse model to deliver IL-10 (anti-inflammatory cytokine), (an antibody blocking the inflammation-promoting activity of TGF-β) or a combination of both through subcapsular injection in the injured kidney. The results showed reduced apoptosis, macrophage infiltration, and fibrosis following both IL-10 and anti-TGF-β administration. Paradoxically, the combined dosage of both cytokines led to opposite effects [61].

However, the lack of electrical conductivity and low mechanical strength has limited biomedical applications of NHs for skeletal muscles, neural cells, and cardiac muscles. Host–guest chemistry dependent hybrid NHs have gained importance as they completely overcome these pitfalls and generate scaffolds of a biological nature with tunable mechanical and electrical characteristics [62].

9 NHs as implantable biosensors

The invention of biosensors has shown to be very helpful in various fields, in industries, such as agriculture, food safety, homeland security, bioprocessing, and environmental and industrial monitoring. Besides these, biosensors have seen a high potential for growth in biosensing and biomedical engineering [63].

Various implantable devices such as heart valves, pacemakers, catheters, stents, scaffolds have been developed in recent years. Implantable biosensors can perform well within the body and are able to continuously monitor patients for an extended period without any intervention. One of its applications can be seen in the monitoring of blood glucose levels in diabetic patients using a glucose biosensor [64, 65]. The first ever biosensor application was seen after the invention of a glucose biosensor based on an oxygen electrode by Leland Clark in the year 1962 [66].

Blood glucose level sensing has been a research topic with much deliberation. The implications are obvious and prove a boon to the patients. Optical biosensing technologies are beneficial as they provide for continuous non-invasive analyte detection post-implantation [67]. Gant et al. reported photopolymerization of an aqueous solution of N-iso pro-polyacrylamide (NIPAAm), polysiloxane colloidal nanoparticles and N-vinylpyrr-olidone (NVP) to deliver an NH, which is stable under in vivo conditions. The NH showed good glucose diffusion, robust mechanical strength, and in vitro cell release upon thermal cycling. Though further research is required to determine the necessary duty cycle to promote optimal glucose diffusion while limiting cell adhesion and to assess in vivo functionality, the in vitro cell adhesion rates were found to be promising [67].

10 NHs for biorobotics

Many scientists and researchers are predicting that combination of carbon-based NHs and cell-laden elastomers will make possible breakthrough progress in the field of soft biorobotics due to enhanced controlled actuation. 3D printing of intricate neural circuits or strong hybrid skeletal muscle tissue from carbon-based hydrogel nanocomposites has captured the imagination of prospective researchers. It is hypothesized that the introduction of these parts into hybrid creatures might lead to the manufacturing of new synthetic life-like forms with cognitive abilities and exceptional locomotive strength [68]. In the realm of biorobotics, these engineered nanohydrogels emulate biological tissues and organs, opening exciting avenues for a diverse range of applications. Researchers are pioneering in biorobots based on nanohydrogels capable of executing tasks like drug delivery, tissue restoration, and even minimally invasive surgeries with unprecedented precision. These biorobots exhibit the ability to respond to external cues, navigate intricate biological environments, and engage with living cells, all while minimizing harm and augmenting biocompatibility. As the field of nano hydrogel-based biorobotics continues to progress, it holds tremendous potential to revolutionize healthcare, diagnostics, and our overall comprehension of biological systems at the nanoscale [69].

11 NHs for cell/tissue regeneration

Clinical products for regenerative procedures and cell therapy require crosslinking biopolymers that are compatible with, the encapsulation of healthy pluripotent cells and injection into tissues. This objective can be met with the formulation of nanocomposite hydrogels [70]. Thermoresponsive sol–gel interchangeable hydrogels have been synthesized for cell delivery and tissue regeneration. Typically, they are liquid at ambient temperature and gel at 37 °C [71]. Lee et al. reported the manufacturing of a hydrogel with the surface of chemically formed micropatterns (circles/squares with a diameter of 200 μm), on which mesenchymal stem cells were selectively attached and formed a monolayer. This NH is capable of thermally controlled expansion. As the temperature decreased from 37 to 4 °C, the cell monolayer detached rapidly and assembled to form spheroids with consistent size. Cell spheroids are known to mimic accurate cell responses and interaction; thereby having immense potential to serve as an in vivo model [72].

The nervous system is devoid of extensive regenerative capacity to heal any damage. It usually requires external interference for healing. Electroconductive hydrogels, with exceptional electromechanical properties, can be used for such nerve regeneration. Xu et al. formulated an electroconductive hydrogel by in situ chemical polymerization of carboxymethyl chitosan (CMCS) and poly(3,4-ethylenedioxythiophene) (PEDOT) with the former ingredient acting as a biodegradable base macromolecular network and the latter as a conductive polymer layer. The resultant NH exhibited enhanced mechanical strength, conductivity, and biocompatibility, all of which can be considered potential materials for neural tissue engineering [73].

Patients with volumetric muscle loss (VML) require aid for recovering the structure and contractile ability of the lost muscle tissue. Gilbert-Honick et al. demonstrated the ability of novel electrospun fibrin hydrogel scaffolds seeded with murine myoblasts to regenerate the structurally and functionally viable muscle mass and thus, these scaffolds offer a promising treatment option for patients with VML [74].

Artificial skin-like biocompatible materials have become popular in the scientific community for their broad applications in artificial intelligence, soft robotics, and wearable devices. Lei et al. reported formulation of a novel bioinspired mineral hydrogel as a capacitive ionic skin sensor that is mechanically amenable to dynamic and curved surfaces, recyclable, and autonomously self-healable. The ionic skin also exhibits very high-pressure sensitivity (up to 1 kPa) that allows a gentle finger touch, motion, and even small water droplets to be detected. The nanocomposite hydrogel-based ionic skin exhibits great potential in applications such as human/machine interactions, artificial intelligence, wearable devices, and personal healthcare. Further, it may also promote the development of next-gen soft, stretchable, and mechanically adaptable intelligent skin-like devices [75].

12 NHs for tissue engineering

In cases of whole organ/tissue failure, there exist options such as repair, replacement with synthetic or natural substitute, or regeneration. Tissue repair or replacement with a compatible substitute is limited to those situations where implants or surgical methods have achieved success. Tissue engineering holds great potential for the regeneration of failed tissue/organs. Hydrogels have become extensively studied matrices for use as tissue engineering scaffolds as it contains pores large enough to accommodate living cells, and they can be designed for releasing growth factors and creating pores into which living cells may penetrate and proliferate [76]. Hydrogels can be engineered to copy the extracellular environment of the body's tissue in ways that enable their use in medical implants, drug-delivery devices, and biosensors [77].

13 NHs as a haemostat and wound healing agent

Skin is the largest organ of the human body with numerous functions to perform which are essential for our very survival. The primary function of this organ is to act as the first line of defense against all types of environmental insults such as harmful chemicals, pathogenic organisms, radiation, etc. It also performs physiological functions such as regulation of moisture loss and maintenance of body temperature [78]. Epidermal wounds, as the initial offense to the skin, breaks open the first guard of defense against additional environmental insults. Secondly, if the wound persists, it forms a breeding ground for multiple pathogens that feed off the body fluids and further worsens the condition. Hence, for any medical procedure to be successful, wound healing is of utmost importance [79]. Established Wound care techniques include healing procedures such as wound dressings and wound vacs, draining, debridement, application of unna boots and total contact casts [78, 80]. However, in cases of open gaping wounds, complete healing must confer refilling the tissue gaps with newly formed tissue. An efficient wound healing technique clotting the blood flow and supporting the growth of healthy new tissue over the wound cavity is still an elusive objective to be accomplished. However, some organisms retain the ability of tissue regeneration throughout adult life [81]. Importunate dermal wounds (e.g. infected diabetic foot ulcers) represent a most important socio-economic issue in developing countries such as India, attributed to its high healthcare costs. Thereby, cost-effective and efficient strategies of wound healing methods need to be developed [82]. Salehi et al. reported positive impacts of nano zeolite/starch thermoplastic hydrogels on wound healing [83]. Lustosa et al. reported the production of a carboxymethyl cellulose-based hydrogel containing in situ-formed silver nanoparticles [84]. Some authors have also reported formulation of silver oxide nanoparticles embedded in silk fibroin spun by the application of microwave technology with antibiotics and synergistic wound healing activity [85]. Though these wound healing techniques come with promising results, they have limited application as in vivo wound dressings containing silver nanoparticles have restricted use due to the inherent toxicity of silver [86]. Secondly, some of the dressings are cost-intensive, thereby limiting the user access. Hence, there is a definite need for development of a holistic wound dressing technology that would mitigate all possible risks and would come at an affordable price. Furthermore, the production of nanoparticles is a reduction reaction, which may be undertaken via chemical or biological pathways. The chemical production of nanoparticles does come with a certain degree of toxicity. Globally, researchers have been trying to formulate a holistic wound healing technology by application of nanoparticles. Singla et al. reported formulation of cellulose nanocrystal composite [triggering expression of essential growth factors such as fibroblast growth factor (FDF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF)] along with silver nanoparticles (for antimicrobial activity) [86]. However, the presence of silver nanoparticles limits the usage as discussed earlier. Hence, the development of a healthcare aid with minimal impact on the environment and human beings is the call of the hour. Recently, people have been focusing on the development of an eco-friendly biological procedure for the production of nanoparticles for the formation of NHs [9, 87,88,89,90]. The aim is to develop a method of hydrogel formulation which being a cure for the problem, is also environment friendly and not toxic in nature.

Human umbilical cord mesenchymal stem cells (HUCMSC) derived exosomes in polyvinyl alcohol (PVA)/ alginate nanohydrogel scaffolds promoted wound healing in diabetic rats by enhancing angiogenesis, cell proliferation, migration, and expediting the wound healing process [91]. Baicalin-loaded nanohydrogels exhibited excellent biocompatibility and effectively countered hydrogen peroxide-induced toxicity, restoring normal cellular conditions. In vivo, studies in mice demonstrated the potential of baicalin-loaded nanohydrogel for skin restoration and inhibiting inflammatory markers (i.e., myeloperoxidase, tumor necrosis factor-alpha, and oedema) [92].

Injectable nanohydrogels have attracted significant interest in the recent past due to their versatility. Giriraj et al. reported a nanocomposite nanohydrogel made of natural polysaccharides, k-carrageenan, and nanosilicates exhibit high mechanical stiffness and good porosity. When vascular endothelial growth factor (VEGF) was added, VEGF-loaded hydrogel improved cell adhesion, reduced blood clotting time and supported in vitro tissue regeneration [93].

14 Cancer therapy

Cancer is one of the leading causes of death globally. In 2022, there were nearly 20 million new cases and 9.7 million cancer-related deaths worldwide. By 2040, the number of new cancer cases per year is projected to rise to 29.9 million, with cancer-related deaths expected to reach 15.3 million [94]. Regrettably, cancer is a highly diverse disease at the tissue level, posing a significant challenge for its precise diagnosis and subsequently, the effectiveness of treatment. Multiple treatment avenues are available for cancer, and their selection hinges on factors such as the cancer type, its level of malignancy, and the stage of its progression. Conventional cancer treatment approaches encompass surgical interventions for the physical removal of cancer, chemotherapy employing systemic anti-cancer drugs, and radiotherapy utilizing ionizing radiation and charged particle beams to eliminate cancer cells [95].

Nanohydrogel-based Cancer therapy represents a promising frontier in the battle against cancer. Nanohydrogels, composed of water-swollen polymer networks at the nanoscale, offer a versatile platform for targeted drug delivery and therapy. By encapsulating anticancer drugs within these nanohydrogels, researchers can achieve precise control over drug release kinetics and improve drug stability, reducing side effects and enhancing therapeutic efficacy [95]. Furthermore, the flexibility of nanohydrogels allows for surface modification with targeting ligands that can specifically bind to cancer cells, enabling the selective delivery of drugs directly to the tumor site while sparing healthy tissues [96].

Furthermore, nanohydrogels facilitate the application of combination therapy by integrating multiple therapeutic agents, including chemotherapeutics, immunotherapeutics, or phototherapeutics as reviewed by Qin et al. harnessing the versatility of nanohydrogels as platforms to achieve synergistic therapeutic outcomes [97]. Hydrogels, being highly proficient drug carriers possess the capacity to regulate both drug loading and drug release while making them a valuable contributor to cancer drug delivery with enduring therapeutic impacts. The natural approach towards the eradication of cancer involves targeting cancer cells. Through mechanisms like the Enhanced Permeability and Retention (EPR) effect and active targeting, modified nanocarriers like nanoparticles (NPs), dendrimers, or carbon nanomaterials (CNMs) that can access cancer cells as well as release chemical drugs or biomaterials [98].

15 Artificial skin

The skin, our body's largest organ, plays a pivotal role as the initial fortress against external bacterial threats. In case of severe burns, the resilience of skin put an extreme test. The intense heat and damage inflicted by such burns often lead to irreparable harm. Tragically, this results in the skin losing its inherent capacity for self-healing, thereby underscoring the profound impact of such injuries on the body's protective and sensory frontline [99].

In a pioneering effort by Yang et al., bionic amphoteric ionic nanocomposite hydrogels were developed. This involved the incorporation of an abundance of amphoteric ionic groups and inorganic salts to ensure robust ionic conductivity. The outcome of this innovation is truly remarkable as these hydrogels not only exhibit enhanced adhesion capabilities when applied to diverse substrates but also boast exceptional mechanical flexibility, impressive transparency, and remarkable stretchability. These characteristics collectively open up exciting possibilities for advancing the intelligence and functionality of artificial skin [100].

In a significant development, Lei et al. and collaborators introduced an innovative ionic skin during the 2nd International Conference on Biological Engineering and Medical Science. This groundbreaking creation, fashioned from bionic hydrogels, effectively retains moisture to uphold humidity levels, facilitates information transmission and sensing via mineral ions, and facilitates point-to-point non-invasive treatments marked by outstanding therapeutic effectiveness and heightened sensitivity [101]. Liu et al. engineered a biomimetic cellulose nanocomposite hydrogel, resembling skin-like properties, through the cross-linking of Ag/TA@CNC nanohybrids with PVA chains [102].

16 Artificial blood vessel

Numerous researchers have demonstrated the potential of 3D printing in fabricating artificial blood vessels as a promising avenue for treating cardiovascular and cerebrovascular diseases. Nonetheless, the existing 3D printing techniques for artificial blood vessels have yet to establish a standardized and comprehensive procedure. This deficiency has led to inadequate control over the shaping of these artificial blood vessels, thereby significantly impairing the quality of vascular structure formation [102].

Stretchability in hydrogels has made significant strides in the twenty-first century. However, the challenge of functionalization has persisted, often resulting in the degradation of their original mechanical properties due to the incorporation of new functional monomers. To address this issue, researchers utilized a muscle-inspired coating technique to immobilize dopamine-transplanted heparin onto alginate/polyacrylamide dual network hydrogels. The outcome was the creation of heparinized hydrogels, which notably enhanced the adhesion affinity between blood cells and blood endothelial cells. Deng et al. innovatively engineered a remarkably stretchable hydrogel characterized by ultra-high hemocompatibility and preserved mechanical integrity. Additionally, the incorporation of a mussel-inspired coating further enhanced the mechanical strength of these hydrogels, positioning them as promising candidates for research in the development of contractible artificial blood arteries [103].

17 Artificial bones

Severe trauma, bone tumors, osteomyelitis, and various other factors leading to bone loss are frequently encountered in the field of orthopedics. Hydrogels, as injectable biomaterials, have witnessed substantial advancements in this domain. These advancements include the utilization of acyl-linked ammonia bond crosslinking, non-covalent crosslinking, and the Diels–Alder (DA) click covalent crosslinking method [104].

Bai et al. have reported that inspired by the intrinsic relationship between the natural structure of bones and their functionality proposed an innovative mineral-organic adhesive designed to provide durable, water-resistant bonding and facilitate guided bone regeneration [99, 104]. By employing an innovative mineral-organic bone adhesive, a novel design approach has been suggested for achieving resilient waterproof fixation and guiding the regeneration of bone tissue [99].

18 Nanohydrogel in dental application

In dental caries treatment, materials like resin, glass ionomers, fluoride coatings, and hydrogels have been commonly utilized. Hydrogels, in particular, have garnered significant interest because of their outstanding biocompatibility, predictable degradation rate, adjustable mechanical properties, and elasticity [105]. Hydrogels can fill damaged areas and support remineralization by stimulating the extracellular matrix (ECM) and delivering a range of factors [106]. In the past decade, numerous tissue engineering methods have emerged to address the challenges of rebuilding dental pulp in regenerative endodontic procedures [107,108,109]. Various scaffold materials have been examined, encompassing natural and synthetic polymers, co-polymers, hydroxyapatite/tricalcium phosphate powders, self-assembling peptide systems, platelet-rich plasma, and decellularized extracellular matrices [105, 110]. However, they only partly meet the required materiobiological criteria for dental pulp (DP) regeneration, which involve structural design, low cytotoxicity, host-driven degradation, and tissue-specific ECM replacement. A dental use injectable fibrin hydrogel was developed to support DP-MSC viability and ECM deposition, but it lacked antimicrobial properties [111].

A nanocomposite scaffold was designed made of fibrin hydrogel supplemented with clindamycin (CLIN) loaded polylactic acid (PLA) NPs as PLA-NPs are biodegradable, biocompatible and has low immunogenicity while CLIN is a versatile antibiotic choice in endodontics due to its broad-spectrum activity, suitability for patients allergic to beta-lactam antibiotics, availability in oral forms, clinical effectiveness, and consideration of individual patient needs [107, 112].

19 Stimuli-responsive hydrogels

Stimuli-responsive hydrogels are advanced materials designed to change their properties in response to specific external or internal triggers. These triggers can include changes in temperature, pH, light, or the presence of ions, enzymes, or biomolecules. Their ability to adapt to changing conditions makes stimuli-responsive hydrogels a versatile and promising area of research and development with significant potential for improving healthcare, materials science, and various industries. There are two types of stimuli—Internal stimuli and External stimuli [113, 114].

19.1 Internal stimuli

Internal stimuli-responsive hydrogels are a class of smart materials that undergo controlled changes in their properties and behavior in response to physiological or environmental cues. These hydrogels are engineered to respond to internal triggers like changes in pH, enzymes, glucose levels, or ions [115]. For example, a glucose-responsive hydrogel electrode, employing FET (field effect transistor) principles, was optimized using HEMA(2-hydroxyethylmethacrylate)/VPBA (vinyl phenylboronic acid) copolymerized hydrogels. It demonstrated high sensitivity, prevented nonspecific adsorption of albumin, and is intended for wearable devices to detect glucose in sweat, saliva, and tears. The FET biosensor platform holds promise for highly sensitive detection of low glucose concentrations in biological fluids [116].

19.2 External stimuli

External stimuli offer the advantage of mitigating interpatient variability, as they allow for precise control of drug release by external factors. This means that, regardless of individual patient differences, drug release can be finely tuned and tailored to specific needs, ensuring more consistent and effective treatment [117]. For example, utilizing a novel CS-g-PNIPAAm {chitosan-graft-poly(N-isopropyl acrylamide)} copolymer, cryogels were developed in combination with PVA for topical antifungal application. This innovative formulation harnesses the copolymer's unique properties, including biocompatibility and stimuli-responsive behavior. The inclusion of PVA enhances structural integrity and flexibility, ensuring effective and prolonged contact with the affected area. This approach represents a promising advancement in topical antifungal therapies, offering improved treatment options for fungal infections [118]. The comprehensive analysis of Type of Stimuli-Responsive Hydrogel and responsive mechanisms and applications is shown in Table 3.

Table 3 Exploring stimuli-responsive hydrogels and comprehensive analysis of types, origins, polymers, responsive mechanisms, and applications
Full size table

20 Discussion

The review of advancements in nanocomposite hydrogels has revealed significant progress in their development and biomedical applications. The key findings of this review highlight the potential of nanocomposite hydrogels to revolutionize various biomedical fields, including drug delivery, tissue engineering, biosensing, wound healing, artificial bones, blood vessels, and cancer therapy, etc. The development of nanohydrogels has overcome the limitations faced in the biomedical field, providing a biocompatible and bioavailable alternative. Nanohydrogels have demonstrated excellent therapeutic activity at targeted sites, reducing the frequency of drug administration and peak concentrations, thereby decreasing harmful side effects [122]. Their applications in drug delivery systems and biological sensors have also shown promise [123]. Hydrogels have been widely studied for tissue regeneration and their potential in this field is significant [124]. As a study by Bonferoni et al., they promote cell growth and tissue regeneration, making them an attractive option for tissue repair and replacement [125]. Furthermore, hydrogels have been used in cancer therapy, demonstrating efficacy in targeting and inhibiting tumor growth suggested by Lu et al. [2] The implications of these findings are significant, suggesting that nanocomposite hydrogels could play a critical role in the development of new biomedical technologies. Their potential in drug delivery, cancer therapy, tissue regeneration, biosensing, and wound healing makes them an attractive option for various biomedical applications. Recent studies have also highlighted the potential of nanocomposite hydrogels in fabrication and bioprinting by Loukelis et al. and their potential in drug delivery and tissue engineering by Thang et al. [126, 127]. Their biosensing capabilities have also been demonstrated, enabling the detection of biomolecules and ions with high sensitivity and selectivity [128].

The biosensing capabilities of nanocomposite hydrogels have also significant implications, enabling the detection of biomolecules and ions with high sensitivity and selectivity [128]. This could lead to new approaches for disease diagnosis and monitoring. Additionally, the use of nanocomposite hydrogels in wound healing has shown promise in enhancing tissue repair and regeneration, which could lead to new approaches for wound management. Another significant advance in biomedicine in Photo-cross-linkable hydrogels is a significant advancement in biomedicine, allowing for the manipulation of their properties through light exposure to achieve desired parameters [124]. This has led to various biomedical applications, including tissue engineering, regenerative medicine, and drug delivery [124, 129]. Hydrogels have become essential in regenerative medicine, with their rigidity influencing stem cell treatment. Researchers are also exploring the use of 3D hydrogels to simulate muscle, skin, and dermis tissue, maximizing their rigidity qualities. The potential applications of hydrogels are vast and still being explored [124, 130, 131].

Hydrogels have untapped potential, with upcoming research exploring new uses. Examples include chitosan-based growth factor delivery and hybrid materials for elastic cartilage regeneration [132, 133]. Novel hydrogels can also be used as fibers for actuators, artificial adhesives, and tissue engineering, promoting reparative dentinogenesis and providing insights for designing tissue scaffolds [134]. Another study reported by Ei et al. Stimuli-responsive hydrogels are intelligent materials that alter their properties in response to environmental cues, such as temperature, pH, or light. This behavior enables them to release therapeutic agents, change shape, or modify their mechanical properties, making them attractive for biomedical applications, including drug delivery, tissue engineering, and biosensing [114]. The potential of nanocomposite hydrogels in cancer therapy is also significant, with the ability to target and inhibit tumor growth [134, 135]. This could lead to new approaches to cancer treatment, reducing the harmful side effects of traditional chemotherapy [135].

21 Conclusion

In conclusion, nanocomposite hydrogels exhibit immense potential to revolutionize biomedical applications. Their unique combination of nanomaterials and hydrogel matrices enables tailored properties, such as enhanced mechanical strength, biocompatibility, and controlled drug release. These innovations address critical challenges in tissue engineering, wound healing, and drug delivery. The adaptability of nanocomposite hydrogels opens new avenues for personalized medicine and therapeutics. As research progresses, further optimization and understanding of their behavior in physiological environments will unlock even greater possibilities, positioning nanocomposite hydrogels as a forefront solution for advancing healthcare and improving patient outcomes in the rapidly evolving landscape of biomedical sciences.

22 Future prospects and potential gaps

The future prospects of nanocomposite hydrogels in biomedical applications are promising, yet several challenges remain. Scalability of production processes to meet industrial demands while maintaining quality and consistency is a significant problem. Long-term biocompatibility and the potential for immunogenic responses require extensive in vivo studies to ensure safety and efficacy. There is also a need for standardized evaluation methods to compare the performance of different nanocomposite hydrogels objectively. Furthermore, while the multifunctionality of these materials is advantageous, the complexity of their synthesis and the need for precise control over their properties can be a barrier to widespread adoption. Future research should focus on developing cost-effective, scalable synthesis methods and thorough biocompatibility testing. Additionally, exploring the synergistic effects of combining various types of nanoparticles within hydrogels could unlock new functionalities and applications, pushing the boundaries of current biomedical technologies. This broad review aims to guide future research and practical applications, offering visions into the development of next-generation nanocomposite hydrogels for diverse biomedical applications.