Biomaterials-Based Hydrogels for Therapeutic Applications

Abstract

Conventional therapeutic models based on the premise of a universal solution are facing a decrease in efficiency, emphasized by the large number of patients who show resistance or who do not respond positively to classic treatments. This perspective highlights the urgency for more precise approaches based on personalized treatments that are adaptable to the specific complexities and unique challenges faced by each patient. Hydrogels are biocompatible and biodegradable systems for well-controlled and targeted administration of therapeutic agents, being formed by 3D reticulated networks of water-soluble polymeric biomaterials, of natural, synthetic, or hybrid origin, with specific intrinsic and extrinsic properties. Due to the easily adjustable porous structure, hydrogels allow the encapsulation of macromolecular drugs, proteins, small molecules, cells, hormones, or growth factors in the gel matrix and their subsequent controlled release. The biomaterials used, the crosslinking methods, the design, and the functionalization strategies in obtaining hydrogels with improved properties are presented. The different possibilities of application are described transdermally, as dressing materials, oral, ocular, spray-able, or injectable, up to the intracellular level. This chapter extensively investigates the advances and unique advantages of hydrogels that enable effective, noninvasive, personalized treatments and provide greater patient comfort for a wide range of applications.

1. Introduction

In recent years, biomaterials-based hydrogels have emerged as promising platforms for a wide range of therapeutic applications, revolutionizing the landscape of modern medicine. These versatile materials, composed of water-swollen polymer networks, possess unique properties that make them ideal candidates for drug delivery, tissue engineering, regenerative medicine, and diagnostic applications [1, 2, 3, 4, 5]. Biomaterials-based hydrogels offer several distinct advantages for therapeutic applications. Their inherent biocompatibility and ability to interact with biological systems without eliciting adverse reactions make them well-suited for in vivo use. Additionally, hydrogels provide a versatile platform for controlled drug delivery, enabling precise modulation of drug release kinetics and spatiotemporal control over therapeutic delivery. In this era of precision medicine, biomaterials-based hydrogels hold immense promise for targeted therapy and personalized treatment approaches [6]. By incorporating bioactive molecules, growth factors, or cell-adhesive peptides into hydrogel matrices, researchers can create tailored environments that promote tissue regeneration, repair, and remodeling. Furthermore, advancements in 3D bioprinting technology enable the fabrication of complex, biomimetic tissue engineering constructs with precise control over scaffold architecture and cell distribution, offering innovative solutions for organ transplantation, wound healing, and disease modeling [7]. Despite the significant progress made in the field of biomaterials-based hydrogels, several challenges and opportunities for advancement remain. In this context, this chapter aims to provide a comprehensive overview of biomaterials-based hydrogels for therapeutic applications, exploring their design principles, fabrication techniques, biomedical applications, trends, and future prospects.

2. Introduction to biomaterials: bridging science and medicine

Biomaterials, at the intersection of science and medicine, represent a dynamic field of study and innovation with profound implications for healthcare and human well-being. These materials, engineered to interact with biological systems, hold the promise of revolutionizing medical treatments, diagnostics, and therapeutic interventions. At its core, a biomaterial is any substance that interacts with biological systems to produce a desired therapeutic or diagnostic effect. This broad definition encompasses a wide range of materials, from metals and ceramics to polymers and composites, each uniquely tailored to fulfill specific biomedical functions [6]. Biomaterials serve as the building blocks of medical devices, implants, drug delivery systems, tissue engineering scaffolds, and diagnostic tools, enabling advancements in regenerative medicine, personalized healthcare, and disease management (Figure 1).

Figure 1.

Diversity, properties, and applications of biomaterials-based hydrogels.

Biomaterials exhibit several key characteristics that distinguish them from conventional materials:

1. Biocompatibility: Biomaterials must be biocompatible, meaning they are well-tolerated by the body without eliciting adverse immune responses or toxic reactions. Biocompatibility ensures that biomaterials can interact with biological tissues and fluids without causing harm, making them suitable for medical applications [5].

2. Bioactivity: Some biomaterials possess inherent bioactivity, meaning they can interact with biological molecules or promote specific cellular responses. Bioactive biomaterials stimulate tissue regeneration, cell adhesion, or molecular signaling, facilitating healing and repair processes within the body [6].

3. Mechanical properties: Biomaterials must possess appropriate mechanical properties to withstand physiological forces and maintain structural integrity in vivo. These properties vary depending on the intended application, with materials ranging from rigid metals for load-bearing implants to flexible polymers for tissue engineering scaffolds [8].

4. Degradation kinetics: Some biomaterials are designed to degrade over time, either through enzymatic degradation or hydrolytic cleavage of polymer chains. Degradable biomaterials enable temporary support or controlled release of therapeutic agents, followed by gradual integration or resorption within the body [2].

5. Surface modifications: Biomaterial surfaces can be modified to enhance biocompatibility, bioactivity, or functionality. Surface modifications may involve coating with bioactive molecules, tethering of cell-adhesive peptides, or incorporation of drug-releasing nanoparticles, enabling tailored interactions with biological systems [3].

The applications of biomaterials span a wide range of medical fields and disciplines, including:

Implantable medical devices: Biomaterials are used to fabricate orthopedic implants, cardiovascular stents, dental prosthetics, and neural electrodes, providing structural support, mechanical stability, and biocompatibility for long-term implantation within the body [8, 9, 10].

Tissue engineering and regenerative medicine: Biomaterials serve as scaffolds for growing tissues and organs in vitro, enabling tissue regeneration and repair in vivo. Tissue-engineered constructs, composed of biomaterials seeded with cells and growth factors, offer promising approaches for treating injuries, defects, and degenerative diseases [11, 12].

Drug delivery systems: Biomaterials are utilized to design drug delivery vehicles, such as nano/microparticles, hydrogels, and implants, enabling targeted delivery, controlled release, and enhanced bioavailability of therapeutic agents for treating various diseases, including cancer, infectious diseases, and chronic conditions [13].

Diagnostic tools and biosensors: Biomaterials are employed to develop diagnostic assays, imaging contrast agents, and biosensors for detecting biomarkers, pathogens, and disease states. Functionalized biomaterials enable sensitive and specific detection of molecular targets, facilitating early diagnosis, disease monitoring, and personalized medicine [14].

Table 1 summarizes the principal characteristics of biomaterials.

Characteristic	Description
Biocompatibility	Ability to interact with biological systems without eliciting adverse reactions
Mechanical strength	Resistance to deformation or fracture under applied loads
Degradation kinetics	Rate of breakdown or dissolution over time
Surface topography	Physical features at the material interface, influencing cell adhesion and response
Porosity	Pore size and distribution affecting fluid transport, cell infiltration, and tissue ingrowth
Bioactivity	Ability to induce specific cellular responses or tissue regeneration
Tunable properties	Flexibility to adjust mechanical, chemical, or biological properties for specific applications
Sterility	Freedom from microbial contamination or potential for sterilization
Immunogenicity	Likelihood of eliciting an immune response in vivo
Stability	Maintenance of structural and functional integrity over time

Table 1.

Characteristics of biomaterials.

2.1 Importance of biomaterials in medicine

The importance of biomaterials in medicine cannot be overstated, as they play a pivotal role in advancing healthcare in numerous ways. Here are some key reasons why biomaterials are indispensable in the field of medicine:

1. Tissue engineering and regenerative medicine: Biomaterials serve as scaffolds and matrices for the regeneration and repair of damaged tissues and organs. They provide structural support and cues for cell growth, differentiation, and tissue formation, enabling the development of novel therapies for conditions ranging from bone defects to organ failure [5].

2. Medical implants and devices: Biomaterials are essential components of medical implants and devices used for various purposes, including joint replacements, cardiovascular stents, dental implants, and prosthetic limbs. These implants restore function, alleviate pain, and improve the quality of life for millions of patients worldwide [8].

3. Drug delivery systems: Biomaterials are employed in drug delivery systems to enhance the efficacy, safety, and targeted delivery of pharmaceutical agents. By encapsulating drugs within biocompatible carriers, biomaterials enable controlled release, prolonged circulation, and site-specific targeting, thereby optimizing therapeutic outcomes and minimizing side effects [2, 11].

4. Diagnostic and therapeutic imaging: Biomaterials are utilized in contrast agents and imaging probes for diagnostic imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound. These biomaterial-based imaging agents enable enhanced visualization of anatomical structures, pathological changes, and molecular markers, facilitating early detection, accurate diagnosis, and treatment monitoring [15].

5. Biosensors and diagnostics: Biomaterials are integral components of biosensors and diagnostic assays for detecting biomolecules, pathogens, and physiological parameters with unique properties, such as biorecognition, signal transduction, and amplification capabilities. Biosensors enable rapid, sensitive, and specific detection of disease biomarkers [14].

6. Surgical and wound care products: Biomaterials are utilized in surgical sutures, tissue adhesives, and wound dressings to promote hemostasis, wound closure, and tissue healing [16, 17]. These biomaterial-based products enhance surgical outcomes, reduce complications, and accelerate the healing process, improving patient recovery and reducing healthcare costs.

7. Biocompatibility testing and research: Biomaterials serve as valuable tools for studying cell–material interactions, biocompatibility, and tissue responses in vitro and in vivo [5].

8. Personalized medicine and theragnostic: Biomaterials are driving innovations in personalized medicine and theragnostic, which combine diagnostics and therapy into integrated platforms [18, 19]. By incorporating biomaterial-based drug delivery systems with diagnostic imaging modalities and targeted therapies, theranostic approaches enable precise diagnosis, treatment monitoring, and therapeutic interventions tailored to individual patients’ needs.

Table 2 provides a basic overview of the advantages and disadvantages of using biomaterials in medicine.

Aspects	Advantages	Disadvantages
Biocompatibility	Interact well with biological systems; Minimal risk of adverse reactions	Risk of immunogenicity; Potential for foreign body response
Mechanical properties	Tunable mechanical properties for various applications; Mimic natural tissues and organs	May lack sufficient strength or stiffness for certain load-bearing needs
Degradation kinetics	Biodegradable options available for temporary applications; Controlled degradation can facilitate tissue regeneration	Variable degradation rates may affect longevity of implants; Potential for inflammatory response during degradation process
Surface topography	Tailorable surface properties for specific applications; Influence cell adhesion, proliferation, and differentiation	Surface modifications may alter biocompatibility or functionality
Porosity	Porous structures facilitate nutrient and waste exchange; Support cell infiltration and tissue ingrowth	May compromise structural integrity or mechanical properties
Bioactivity	Induce specific cellular responses or tissue regeneration	Potential for unintended biological effects or off-target interactions
Tunability	Flexibility to adjust properties for diverse medical needs	Requires careful optimization and characterization
Sterility	Potential for sterilization to minimize infection risk	Sterilization methods may alter material properties or structure

Table 2.

Advantages and disadvantages of using biomaterials in medicine.

2.2 Overview of different types of biomaterials

Biomaterials encompass a diverse array of materials engineered to interact with biological systems [20, 21, 22]. From synthetic polymers to natural substances, biomaterials offer a rich tapestry of options for addressing various medical challenges.

1. Synthetic polymers offer unparalleled versatility, enabling precise control over mechanical, chemical, and biological properties. Examples include polyethylene glycol (PEG), polylactic acid (PLA), and poly(lactic-co-glycolic acid) (PLGA). Synthetic polymers find applications in drug delivery systems, tissue engineering scaffolds, and medical implants, where their tailored functionalities facilitate targeted therapeutic interventions and tissue regeneration [23, 24].

2. Natural polymers derived from biological sources such as proteins, polysaccharides, and extracellular matrices, natural polymers offer inherent biocompatibility and bioactivity. Collagen, derived from connective tissues, serves as a ubiquitous scaffold for tissue engineering and wound healing. Hyaluronic acid, a glycosaminoglycan found in the extracellular matrix, exhibits excellent lubricating and viscoelastic properties, making it ideal for ophthalmic and orthopedic applications. Natural polymers offer the advantage of mimicking the complexity and biochemical cues of native tissues, fostering cell adhesion, proliferation, and differentiation in regenerative medicine approaches [25, 26].

3. Metals and Alloys renowned for their strength, durability, and biocompatibility, are indispensable in orthopedic and dental implants, cardiovascular stents, and surgical instruments. Titanium and its alloys, such as Ti-6Al-4V, are prized for their excellent corrosion resistance and osseointegration properties, making them ideal for load-bearing implants. Stainless steel, with its high strength and machinability, finds applications in orthopedic fixation devices and cardiovascular stents. Metals and alloys provide structural support and mechanical stability, ensuring the long-term success of implantable medical devices [27, 28].

4. Ceramics characterized by their hardness, biocompatibility, and bioactivity, hold promise for various biomedical applications. Hydroxyapatite, a calcium phosphate ceramic, mimics the mineral composition of bone and serves as a bone graft substitute for promoting osteogenesis and osseointegration. Bioactive glasses, such as silicate-based compositions, exhibit osteoconductive and angiogenic properties, facilitating bone regeneration and tissue repair. Ceramics offer excellent biocompatibility and stability in physiological environments, making them valuable materials for bone substitutes, dental restorations, and tissue engineering scaffolds [29, 30].

5. Composites composed of two or more distinct materials combine the advantageous properties of each component to achieve synergistic effects and to address specific biomedical needs [31, 32]. For example, polymer-ceramic composites merge the flexibility of polymers with the strength and bioactivity of ceramics, offering enhanced mechanical properties and biological performance for bone tissue engineering and dental restorations. Carbon nanotube-reinforced polymers harness the exceptional mechanical strength and electrical conductivity of carbon nanotubes for applications in neural interfaces and tissue engineering scaffolds.

3. Hydrogels

Hydrogels, a fascinating class of biomaterials, hold immense promise for a wide range of biomedical applications. These unique materials, characterized by their high-water content and tunable properties, offer versatility and biocompatibility unmatched by traditional materials. At their core, hydrogels are three-dimensional networks of hydrophilic polymer chains that swell in water but maintain their structural integrity. This unique characteristic endows hydrogels with a sponge-like quality, allowing them to absorb and retain large amounts of water while retaining their shape and mechanical properties. Hydrogels can be synthesized from both natural and synthetic polymers, offering a wide range of options for tailoring their properties to suit specific applications [33, 34].

3.1 Properties of hydrogels

1. High-water content: This property enables hydrogels to mimic the physiological environment, making them ideal candidates for tissue engineering and drug delivery [1].

2. Tunable mechanical properties of hydrogels: These can be precisely engineered by adjusting factors such as polymer composition, crosslinking density, and network architecture. This tunability allows hydrogels to mimic the mechanical properties of various tissues, ranging from soft brain tissue to stiff cartilage, making them suitable for a wide range of applications in regenerative medicine and soft tissue engineering [3].

3. Biocompatibility and bioactivity: Hydrogels exhibit excellent biocompatibility, providing a supportive environment for cell growth, proliferation, and tissue regeneration. Furthermore, hydrogels can be engineered to incorporate bioactive molecules such as growth factors, peptides, and cytokines, enhancing their ability to promote tissue healing and regeneration [34].

4. Swelling and degradation kinetics: Hydrogels swell in response to water uptake, allowing for controlled release of encapsulated drugs or bioactive molecules. Additionally, hydrogels can be designed to degrade over time, either through enzymatic degradation or hydrolytic cleavage of polymer chains. This degradation kinetics can be tailored to match the rate of tissue regeneration, enabling transient support followed by gradual integration into native tissue [33].

5. Responsive behavior: Some hydrogels exhibit responsive behavior to external stimuli such as pH, temperature, and light. These stimuli-responsive hydrogels undergo reversible changes in swelling, mechanical properties, or drug release in response to changes in their environment. This property enables precise control over hydrogel behavior and functionality, opening up new avenues for smart drug delivery systems and tissue engineering scaffolds [6, 26].

3.2 Classification of hydrogels

One key aspect that distinguishes hydrogels is their classification based on their origin and composition.

1. Natural hydrogels are derived from biopolymers found in living organisms, offering inherent biocompatibility and bioactivity [33, 34]. These hydrogels are often sourced from proteins, polysaccharides, and extracellular matrices, which provide a natural scaffold for cellular activities. Examples of natural hydrogels include:

   • Collagen hydrogels: Derived from collagen, the main structural protein in connective tissues, collagen hydrogels closely mimic the composition and properties of native extracellular matrices. These hydrogels offer excellent biocompatibility and promote cell adhesion, proliferation, and tissue regeneration, making them valuable materials for wound healing, tissue engineering, and drug delivery applications [35].

   • Alginate hydrogels: Alginate, extracted from brown seaweed, forms hydrogels through ionic crosslinking with divalent cations such as calcium ions. Alginate hydrogels exhibit high-water content and tunable mechanical properties, making them suitable for applications in cell encapsulation, drug delivery, and tissue engineering [36].

   • Hyaluronic acid hydrogels: Hyaluronic acid, a glycosaminoglycan found in the extracellular matrix, forms hydrogels with excellent viscoelastic properties and biocompatibility. Hyaluronic acid hydrogels are widely used in ophthalmic and orthopedic applications, as well as in skin care products and drug delivery systems [37].

Natural hydrogels offer the advantage of mimicking the complexity and biochemical cues of native tissues, fostering cell adhesion, proliferation, and differentiation in regenerative medicine approaches.

1. Synthetic hydrogels are engineered from synthetic polymers and designed to exhibit tailored functionalities and mechanical properties for specific biomedical applications. Examples of synthetic hydrogels include:

   • Polyethylene glycol (PEG) hydrogels: PEG hydrogels are synthesized from polyethylene glycol, a biocompatible and inert polymer. These hydrogels offer tunable mechanical properties, swelling behavior, and degradation kinetics, making them versatile platforms for drug delivery, tissue engineering, and biosensing applications [24, 38].

   • Poly(N-isopropylacrylamide) (PNIPAAm) hydrogels: PNIPAAm hydrogels exhibit thermoresponsive behavior, undergoing reversible phase transition in response to changes in temperature. Below a critical temperature (lower critical solution temperature, LCST), PNIPAAm hydrogels swell in water, while above the LCST, they collapse and disappear. This unique property enables PNIPAAm hydrogels to be utilized in smart drug delivery systems and tissue engineering scaffolds [39].

   • Polyacrylamide hydrogels: Polyacrylamide hydrogels offer high mechanical strength and stability, making them suitable for applications requiring load-bearing capabilities in tissue engineering, cell culture, and microfluidic devices due to their biocompatibility and ease of fabrication [40].

2. Hybrid hydrogels combine elements of both natural and synthetic polymers, offering synergistic properties and functionalities. These hybrid materials leverage the advantages of natural polymers, such as biocompatibility and bioactivity, while incorporating the tunability and mechanical strength of synthetic polymers. Examples of hybrid hydrogels include [41]:

   • Gelatin-methacryloyl (GelMA) hydrogels are synthesized by chemically modifying gelatin with methacryloyl groups, enabling photocrosslinking and tunable mechanical properties. They combine the biocompatibility of gelatin with the versatility of photopolymerization, making them valuable materials for tissue engineering, 3D bioprinting, and drug delivery applications [7].

   • Chitosan-polyethylene glycol (CS-PEG) hydrogels: CS-PEG hydrogels combine the biocompatibility of chitosan with the tunability of polyethylene glycol, offering a versatile platform for drug delivery and tissue engineering. They exhibit controlled release of encapsulated drugs and growth factors, promoting tissue regeneration and wound healing [17, 38].

   • Cellulose-based hydrogels: Cellulose-based hydrogels incorporate cellulose derivatives with synthetic polymers to create hybrid materials with enhanced mechanical properties and biocompatibility. These hydrogels find applications in wound dressings, drug delivery systems, and tissue engineering scaffolds, leveraging the biodegradability and abundance of cellulose [33].

Hybrid hydrogels harness the synergy between natural and synthetic components, offering a platform for multifunctional and tailored materials with enhanced properties and performance. Natural hydrogels leverage the biocompatibility and bioactivity of biopolymers sourced from living organisms, while synthetic hydrogels offer precise control over properties and functionalities through engineered polymers.

3.3 Factors influencing the design and properties of hydrogels

In the realm of biomaterials, hydrogels stand out as versatile and promising materials with diverse applications in medicine and biotechnology. The design and properties of hydrogels are influenced by numerous factors, ranging from their composition and synthesis methods to environmental conditions and intended applications.

3.3.1 Composition of hydrogels

The composition of hydrogels serves as the foundation for their properties and functionalities, dictating their biocompatibility, mechanical strength, and responsiveness to stimuli. Hydrogels can be composed of natural polymers, synthetic polymers, or hybrid combinations thereof, each offering unique advantages and challenges. By leveraging the advantages of natural polymers (e.g., biocompatibility) with the tunability of synthetic polymers (e.g., mechanical strength), hybrid hydrogels provide versatile platforms for biomedical applications [42, 43].

3.3.2 Crosslinking methods

The crosslinking method, which is essentially the gel structure forming reaction, employed during hydrogel synthesis plays a critical role in determining the network architecture, mechanical properties, and responsiveness of hydrogels. Various crosslinking strategies, including physical, chemical, and biological methods, offer distinct advantages and limitations for tuning hydrogel properties [44]. Chemical crosslinking methods require precise control of reaction conditions, stoichiometry, and reaction kinetics to achieve desired crosslink densities and network structures. Physical crosslinking techniques involve optimization of environmental parameters to induce gelation [45].

• Physical Crosslinking: Physical crosslinking methods, such as temperature-induced gelation, ionotropic gelation, and self-assembly, rely on noncovalent interactions to form the hydrogel network. These methods offer simplicity and reversibility, enabling controlled gelation and responsive behavior, as well as lower mechanical strength and stability compared to chemically crosslinked hydrogels.

• Chemical Crosslinking: Chemical crosslinking methods, such as photopolymerization, Michael addition, and click chemistry, involve the formation of covalent bonds between polymer chains to create a stable hydrogel network. These methods offer precise control over crosslink density and mechanical properties, facilitating the customization of hydrogel stiffness, degradation kinetics, and drug release profiles.

• Biological Crosslinking: Biological crosslinking methods, such as enzymatic crosslinking and cell-mediated gelation, harness biological agents to induce hydrogel formation and remodeling. These methods offer compatibility with living cells and tissues, enabling in situ gelation and dynamic interactions with the biological environment.

3.3.3 Environmental conditions

The properties and behavior of hydrogels are influenced by environmental conditions such as temperature, pH, and ionic strength, which can trigger changes in swelling, mechanical properties, and drug release kinetics [46].

• pH Responsiveness: pH-responsive hydrogels, such as poly(acrylic acid) (PAA) hydrogels, exhibit changes in swelling behavior and mechanical properties in response to variations in pH. By incorporating pH-sensitive moieties into the hydrogel network, researchers can design hydrogels that respond to acidic or alkaline environments, enabling applications in drug delivery, biosensing, and wound healing.

• Ionic strength and solvent composition: Hydrogel swelling, and network properties can be influenced by variations in ionic strength and solvent composition. By adjusting the concentration of ions or solvent polarity, researchers can modulate hydrogel swelling behavior, drug release kinetics, and mechanical properties, offering opportunities for tailored hydrogel design and optimization.

4. Biomaterials for drug delivery

The convergence of biomaterials science and pharmaceuticals has given rise to a revolutionary approach in healthcare: drug delivery systems. These systems utilize biomaterials as carriers to transport therapeutic agents to specific targets within the body, offering precise control over drug release kinetics, bioavailability, and therapeutic efficacy [2, 47, 48, 49, 50].

Biomaterial-based drug delivery systems are engineered to overcome biological barriers that limit the efficacy of conventional drug formulations. Nanoparticle carriers, for example, can bypass the blood-brain barrier to deliver drugs to the central nervous system, offering new treatment avenues for neurological disorders such as Alzheimer’s disease and brain tumors [51]. Similarly, hydrogel-based delivery systems can penetrate the tumor microenvironment to deliver therapeutics to cancer cells, overcoming obstacles such as hypoxia and interstitial fluid pressure.

To address the challenges associated with conventional therapeutic models, there is a growing need for personalized approaches in biomaterials-based hydrogel design and application. Key strategies for advancing personalized hydrogel-based therapies include:

• Integration of patient-specific parameters, such as tissue characteristics, immune response, and genetic factors, into biomaterial selection processes to optimize biocompatibility and therapeutic efficacy [43].

• Development of targeted drug delivery systems that incorporate patient-specific factors, such as tumor biomarkers or disease characteristics, to achieve site-specific drug release and enhance therapeutic outcomes [52].

• Customized fabrication of hydrogel scaffolds with tailored mechanical properties, bioactive cues, and degradation kinetics to promote tissue-specific regeneration and integration [53].

4.1 Importance of drug delivery in medicine

In the realm of modern medicine, drug delivery stands as a cornerstone of therapeutic interventions, facilitating the precise administration of pharmaceutical agents to targeted sites within the body. From alleviating symptoms to curing diseases, drug delivery systems play a pivotal role in optimizing therapeutic outcomes while minimizing adverse effects. Conventional drug delivery systems can have many side effects because they have poor bioavailability, variations in plasma drug levels and do not demonstrate sustained release. Also, some excipients of synthetic origin contained in classic medicines, such as coloring agents, perfumes, antioxidants, anti-caking agents, binding agents, solvents and lubricants, sweeteners, flavoring agents, preservatives or solubilizing agents, can induce nausea, dizziness, headaches, can be metabolized in certain organs, and can promote the onset or worsening of certain diseases over time. For this reason, modern treatment systems based on biomaterials, of natural origin, with improved efficiency and minimal or absent side effects, are at the top of scientific research in the biomedical field.

Drug delivery is a critical component of medical treatment, influencing the efficacy, safety, and patient compliance of pharmaceutical interventions. Several factors underscore the importance of drug delivery in medicine:

1. Drug delivery systems enable the controlled release and targeted delivery of pharmaceutical agents to specific sites within the body, maximizing therapeutic efficacy while minimizing systemic side effects. By optimizing drug concentrations at the site of action, drug delivery systems enhance the effectiveness of treatments for various diseases, ranging from cancer to infectious diseases.

2. Drug delivery systems offer convenience and ease of administration, enhancing patient compliance with prescribed treatment regimens. Whether in the form of oral tablets, transdermal patches, or injectable formulations, optimized drug delivery systems streamline medication administration, reducing the burden on patients and improving treatment adherence.

3. Drug delivery systems can be designed to provide sustained release or prolonged action of pharmaceutical agents, maintaining therapeutic drug levels in the body over an extended period. By controlling drug release kinetics, drug delivery systems optimize pharmacokinetics and pharmacodynamics, ensuring continuous and effective treatment while minimizing fluctuations in drug concentrations.

4. Advances in drug delivery technologies have paved the way for personalized medicine approaches, tailoring treatment regimens to individual patient characteristics and disease profiles. By incorporating patient-specific factors such as genetic polymorphisms, disease biomarkers, and pharmacokinetic parameters, drug delivery systems enable precision medicine strategies that optimize therapeutic outcomes and minimize adverse events.

5. Drug delivery systems can overcome biological barriers such as the blood-brain barrier, gastrointestinal mucosa, and tumor microenvironment, enabling the delivery of therapeutics to otherwise inaccessible sites. By incorporating targeting ligands, nanoparticles, or drug conjugates, drug delivery systems enhance drug penetration and bioavailability, overcoming physiological barriers and improving treatment efficacy for challenging conditions.

6. Drug delivery systems enable the co-delivery of multiple therapeutic agents, facilitating combination therapies that target multiple pathways or disease processes simultaneously. By encapsulating drugs within the same carrier or incorporating multiple drug-loaded nanoparticles, drug delivery systems enhance synergistic effects, overcome drug resistance, and improve therapeutic outcomes for complex diseases such as cancer and infectious diseases.

4.2 Various drug delivery systems

Drug delivery systems encompass a diverse array of technologies designed to optimize the administration, targeting, and release of pharmaceutical agents within the body, enhancing therapeutic efficacy and minimizing side effects [54].

4.2.1 Conventional drug delivery systems

Oral drug delivery remains one of the most common and convenient methods of medication administration. Oral tablets, capsules, and liquid formulations offer ease of use, patient compliance, and widespread availability. These formulations undergo dissolution and absorption in the gastrointestinal tract, delivering drugs to systemic circulation for distribution to target tissues. Modified-release formulations, such as extended-release tablets and gastro-resistant capsules, enable controlled drug release and prolonged therapeutic action, enhancing treatment efficacy and patient convenience.

Transdermal drug delivery systems deliver drugs through the skin for systemic absorption, bypassing the gastrointestinal tract and first-pass metabolism. Transdermal patches, creams, and gels offer sustained release of drugs over an extended period, providing steady plasma concentrations and minimizing fluctuations in drug levels. These systems are commonly used for delivering hormones, analgesics, and cardiovascular medications, offering advantages such as improved patient compliance, reduced systemic side effects, and avoidance of gastrointestinal irritation.

Inhalation drug delivery systems deliver medications directly to the lungs for rapid absorption and therapeutic effect. Metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers are commonly used for delivering bronchodilators, corticosteroids, and other respiratory medications. Inhalation therapy offers targeted delivery to the site of action, rapid onset of action, and reduced systemic exposure, making it an effective approach for managing respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

4.2.2 Advanced drug delivery systems

Nanoparticle-based drug delivery systems utilize nanoscale carriers such as liposomes, polymeric nanoparticles, and lipid nanoparticles to encapsulate and deliver drugs to target tissues. These carriers offer advantages such as enhanced drug solubility, prolonged circulation time, and targeted delivery to specific cells or tissues. Nanoparticle formulations enable the controlled release of drugs, reduce systemic toxicity, and improve therapeutic efficacy, making them promising platforms for cancer therapy, gene delivery, and targeted drug delivery to the brain.

Hydrogel-based drug delivery systems utilize hydrophilic polymer networks to encapsulate drugs and release them in a controlled manner. These systems are used for localized drug delivery to tissues, wound healing, and sustained release of therapeutic agents. Injectable hydrogels offer minimally invasive delivery routes and conformal contact with tissues, making them suitable for tissue engineering, regenerative medicine, and controlled drug release applications.

Implantable drug delivery devices are surgically implanted within the body to deliver drugs over an extended period. These devices include drug-eluting stents, subcutaneous implants, and intravitreal implants, offering localized drug delivery and sustained release of therapeutics. Implantable devices provide advantages such as improved patient compliance, reduced dosing frequency, and enhanced therapeutic efficacy, particularly for chronic conditions requiring long-term treatment.

Targeted drug delivery systems aim to deliver drugs selectively to diseased tissues or cells while minimizing exposure to healthy tissues. These systems utilize targeting ligands, antibodies, or stimuli-responsive materials to achieve site-specific drug delivery. Targeted drug delivery offers advantages such as increased drug accumulation at the target site, reduced systemic toxicity, and enhanced therapeutic efficacy. Examples include antibody-drug conjugates, targeted nanoparticles, and stimuli-responsive hydrogels for cancer therapy, inflammatory diseases, and infectious diseases.

4.3 Advantages of using hydrogels for drug delivery

Hydrogels, with their unique properties and versatile characteristics, have emerged as promising platforms for drug delivery applications. From controlled release to targeted delivery, hydrogels offer numerous advantages that make them attractive for pharmaceutical formulations [55]. Hydrogels offer precise control over drug release kinetics, enabling sustained, controlled release of pharmaceutical agents over extended periods. The porous structure of hydrogels allows drugs to be encapsulated within the polymer matrix, from which they can diffuse or be variably released in response to external stimuli, from zero-order kinetics to pulsatile or stimuli-responsive release.

Hydrogels can be engineered to achieve targeted drug delivery to specific tissues or cells within the body. Functionalization of hydrogels with targeting ligands, antibodies, or peptides enables selective binding to receptors or biomarkers expressed on target cells, enhancing drug accumulation and therapeutic efficacy while minimizing off-target effects. Targeted drug delivery using hydrogels offers advantages such as increased drug bioavailability, reduced systemic toxicity, and enhanced treatment outcomes for diseases such as cancer, inflammation, and infectious diseases.

5. Design and formulation of biomaterial-based hydrogels

5.1 Engineering hydrogel composition

The design of biomaterial-based hydrogels begins with the selection and engineering of hydrogel composition. Natural polymers such as collagen, alginate, hyaluronic acid, and chitosan offer inherent biocompatibility and bioactivity, mimicking the extracellular matrix of native tissues. Synthetic polymers such as polyethylene glycol (PEG), polyacrylamide (PAA), and poly(N-isopropylacrylamide) (PNIPAAm) offer precise control over mechanical properties, degradation kinetics, and responsiveness to stimuli. Hybrid hydrogels, combining elements of natural and synthetic polymers, offer synergistic properties that enhance biocompatibility, mechanical strength, and tunability.

5.2 Crosslinking strategies for hydrogel formation

The formation of hydrogels relies on crosslinking strategies that create stable networks of polymer chains. Various crosslinking methods, including physical, chemical, and biological approaches, offer distinct advantages and limitations for hydrogel synthesis. By selecting appropriate crosslinking strategies, researchers can tailor hydrogel properties such as mechanical strength, swelling behavior, and degradation kinetics to meet specific application requirements.

5.3 Modulating hydrogel properties and functionality

The properties and functionality of hydrogels can be modulated through various strategies, including molecular design, polymer modification, and incorporation of bioactive molecules. By tuning parameters such as polymer concentration, crosslinking density, and network architecture, researchers can control hydrogel stiffness, porosity, and water retention capacity. Stimuli-responsive hydrogels, designed to undergo reversible changes in response to external stimuli such as temperature, pH, or light, offer opportunities for on-demand drug release and dynamic modulation of hydrogel properties.

5.4 Methods for preparing hydrogels

5.4.1 Polymerization techniques

Free radical polymerization: Free radical polymerization is a commonly used method for synthesizing hydrogels from monomers such as acrylic acid, acrylamide, or methacrylate derivatives. Initiators such as ammonium persulfate (APS) and N,N,N′,N′-tetramethylethylenediamine (TEMED) are used to initiate polymerization, leading to the formation of crosslinked polymer networks [56].

Crosslinking Polymerization: Crosslinking polymerization involves the crosslinking of preformed polymer chains to create hydrogel networks. Crosslinking agents such as glutaraldehyde, genipin, or poly(ethylene glycol) diacrylate (PEGDA) are used to link polymer chains via covalent bonds, resulting in hydrogels with tunable mechanical properties and degradation kinetics [57].

5.4.2 Physical gelation methods

Temperature-induced gelation: Temperature-induced gelation relies on the reversible sol-gel transition of polymers in response to changes in temperature. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm) undergo a phase transition near their lower critical solution temperature (LCST), resulting in the formation of hydrogels at elevated temperatures and solubilization at lower temperatures [58].

Ionic gelation: Ionic gelation involves the crosslinking of polymers via ionic interactions between oppositely charged ions. Polymers such as alginate or chitosan form hydrogels in the presence of multivalent cations such as calcium ions (Ca²⁺), resulting in the formation of stable crosslinked networks [59].

5.4.3 Chemical modification techniques

Functionalization: Hydrogel properties can be modified through chemical functionalization of polymer chains. Functional groups such as carboxylic acids, amino groups, or thiol groups can be introduced onto polymer chains via chemical reactions such as amidation, esterification, or thiolene click chemistry, enabling tailored hydrogel properties and functionalities [60].

Surface modification: Surface modification of hydrogels involves the attachment of bioactive molecules, cell-adhesive peptides, or growth factors onto hydrogel surfaces. Surface modification techniques such as physical adsorption, covalent immobilization, or layer-by-layer assembly enable the creation of bioactive hydrogels with enhanced cell adhesion, proliferation, and differentiation properties.

5.4.4 Solution casting and molding

Solution casting and molding involve the preparation of hydrogel precursor solutions followed by casting into molds and subsequent gelation. This method allows for the fabrication of hydrogel films, discs, or shapes with precise control over size, shape, and thickness.

5.4.5 Electrospinning

Electrospinning is a technique used to fabricate hydrogel fibers with diameters ranging from nanometers to micrometers. Hydrogel precursor solutions are electrospun into fine fibers using an electric field, resulting in the formation of hydrogel mats or scaffolds with high surface area and porosity.

5.4.6 3D printing

3D printing, also known as additive manufacturing, enables the fabrication of complex three-dimensional hydrogel structures layer by layer. Hydrogel precursor solutions are deposited onto a substrate using a computer-controlled nozzle or laser, allowing for the precise spatial patterning of hydrogel materials.

5.5 Characterization techniques

Swelling Ratio Measurement: The swelling ratio of hydrogels, defined as the ratio of swollen weight to dry weight, is often measured to assess hydrogel swelling behavior and water retention capacity.

Mechanical Testing: Mechanical testing techniques such as tensile testing, compression testing, or rheological analysis are used to evaluate the mechanical properties of hydrogels, including stiffness, elasticity, and viscoelastic behavior.

Drug Release Studies: Drug release studies are conducted to assess the release kinetics of therapeutic agents from hydrogel matrices. Techniques such as spectrophotometry, chromatography, or imaging are used to quantify drug release over time.

Biocompatibility Assessment: Biocompatibility assessment involves evaluating the cytotoxicity, cell adhesion, and cell proliferation of hydrogels using in vitro cell culture assays or in vivo animal studies.

Methods for preparing hydrogels encompass a wide range of synthesis, modification, fabrication, and characterization techniques tailored to achieve specific properties and applications. From polymerization techniques to physical gelation methods, chemical modification strategies, and fabrication techniques, researchers and engineers have at their disposal a versatile toolkit for designing and engineering hydrogels with precise control over structure, properties, and functionality [61].

5.6 Incorporation of therapeutic agents into hydrogel matrices

Hydrogels serve as versatile carriers for the encapsulation and controlled release of therapeutic agents, ranging from small molecules to proteins and nucleic acids [62]. By incorporating therapeutic agents into hydrogel matrices, researchers can achieve precise control over drug release kinetics, improve drug stability, and enhance therapeutic efficacy.

5.6.1 Encapsulation techniques

Physical entrapment involves the encapsulation of therapeutic agents within hydrogel matrices through physical interactions such as hydrogen bonding, electrostatic interactions, or hydrophobic interactions. Therapeutic agents are simply mixed with hydrogel precursor solutions before gelation, resulting in a uniform distribution of drugs throughout the hydrogel matrix. Chemical conjugation entails the covalent attachment of therapeutic agents to polymer chains within hydrogel matrices. Functional groups on therapeutic agents and polymer chains are chemically modified to facilitate covalent bonding, ensuring the stable incorporation of drugs into hydrogel networks.

5.6.2 Key considerations

1. Hydrogels and encapsulated therapeutic agents must be biocompatible to ensure compatibility with biological systems and minimize adverse effects on cells and tissues.

2. Encapsulated therapeutic agents should remain stable within hydrogel matrices to maintain drug potency and efficacy throughout the release process.

3. The release kinetics of therapeutic agents from hydrogel matrices should be carefully tuned to achieve desired release profiles, balancing factors such as diffusion rates, degradation rates, and stimuli responsiveness.

5.7 Strategies for controlling drug release from hydrogels

Controlling drug release from hydrogels is crucial for optimizing therapeutic efficacy, minimizing side effects, and achieving desired pharmacokinetic profiles.

5.7.1 Diffusion-controlled release

The structure of hydrogel matrices, including porosity, mesh size, and network density, influences the diffusion of therapeutic agents through the hydrogel network. Tuning these parameters allows for controlled diffusion of drugs and modulation of release kinetics. The concentration of therapeutic agents loaded into hydrogel matrices affects drug release kinetics, with higher loading concentrations typically resulting in faster release rates due to increased concentration gradients.

5.7.2 Degradation-controlled release

Hydrogel degradation kinetics, determined by factors such as polymer composition, crosslinking density, and degradation mechanisms, influence drug release rates. Degradable hydrogels undergo gradual breakdown, releasing encapsulated drugs as the polymer matrix degrades over time. Enzyme-responsive hydrogels incorporate peptide sequences susceptible to enzymatic cleavage within the polymer network. Enzyme activity in the surrounding environment triggers hydrogel degradation and subsequent release of therapeutic agents, enabling spatiotemporal control over drug release.

5.7.3 Stimuli-responsive release

pH-responsive hydrogels undergo structural changes in response to variations in pH, enabling the triggered release of therapeutic agents under acidic or basic conditions. pH-sensitive polymers such as poly(acrylic acid) (PAA) or poly(histidine) (PHis) are commonly used to design pH-responsive hydrogels for targeted drug delivery to specific physiological environments [63]. Temperature-responsive hydrogels exhibit phase transitions in response to changes in temperature, resulting in sol–gel transitions and modulation of drug release kinetics. Thermoresponsive polymers such as poly(N-isopropylacrylamide) (PNIPAAm) undergo reversible phase transitions near their lower critical solution temperature (LCST), enabling the temperature-triggered release of therapeutic agents [64].

5.7.4 External stimuli-responsive release

Light-responsive hydrogels incorporate photoreactive moieties that undergo conformational changes or crosslinking upon exposure to specific wavelengths of light. Light-triggered hydrogel systems enable spatially controlled release of therapeutic agents using light patterning techniques such as photolithography or laser irradiation. Magnetic-responsive hydrogels incorporate magnetic nanoparticles within the polymer matrix, enabling remote control over drug release using external magnetic fields. Magnetic stimuli induce mechanical deformation or swelling of hydrogel networks, facilitating the on-demand release of therapeutic agents at target sites.

6. Biomaterials-based hydrogels in skin tissue engineering, surgical defects, and wound healing

6.1 Role of hydrogels in wound management

The outer layer of the human body, the skin, is our largest organ, and the first defense barrier against harmful environmental influences [65, 66]. It is incredibly versatile and performs many vital functions. The skin has the ability to regenerate itself naturally, but this self-healing ability can be diminished for wounds larger than about 4 centimeters in diameter [67]. Bandages are applied to help the wound healing process and also to protect the wounds from various infections. Currently, a variety of modern products have been commercially launched for wound care, including foams, films, hydrocolloids, hydrogels, and hydrofibers. Hydrogels are ideal wound dressings due to their exceptional biological properties [68, 69, 70, 71]. Dressings based on hydrogels are considered advanced successful systems and particularly useful tools in biomedical practice.

Hydrogels can be designed with a wide variety of characteristics to obtain biocompatible, stable, and bioresorbable polymeric matrices for applied biomedicine such as skin tissue engineering and wound management [72, 73]. A crucial attribute of the use of hydrogels in wound healing is to ensure facile application, long-lasting adhesiveness, and the ability to be easily removed from human skin without causing any damage or leaving traces [74, 75, 76]. In addition, they are considered therapies with great potential to reduce scar formation in skin wounds due to their high water content. As dressing materials, they can be used both for exudative wounds and for dry wounds. The main constraints of medical adhesive hydrogels are the strength to adhere to soft tissue surfaces and the resistance to cyclic stresses in the moist and dynamic environments surrounding the tissues [77]. Hydrogels do not cause irritation, allow the passage of metabolites, and do not interact with biological tissues [78]. Hydrogels are used to transport various drugs to areas affected by wounds, benefiting from their porous, hydrophilic structure [2]. A promising strategy to avoid scar formation following skin injury involves employing a hydrogel as a pro-regenerative matrix combined with growth factors and various cell types to stimulate tissue regeneration. Its adhesive attributes allow it to adhere to hard and soft tissues, being a valuable material in surgery, orthopedics, dentistry, ophthalmology, technical-sanitary instrumentation, or surgical tools [79, 80, 81, 82].

Polysaccharide-based hydrogels used as dressings for wound healing ensure several simultaneous activities to support complete recovery and have the following role [83]:

1. Antioxidant. They lead to the reduction of the level of reactive oxygen species that affect the antioxidant capacity necessary to promote the healing of diabetic wounds. Oxidative stress inhibits healing progress in many categories of skin wounds, such as bacterial infections, erosions, scars, ulcers, burns, or acute trauma.

2. Anti-inflammatory. Inhibition of anti-inflammatory responses is a key factor in wound healing, especially chronic wounds. Incorporating drugs with anti-inflammatory properties into the bioinspired hydrogel matrix is an advantageous approach that helps increase the anti-inflammatory effects.

3. Antibacterial. The incorporation of biomaterials into wound dressings increases their ability to inhibit the growth of a wide spectrum of bacteria and reduces the risk of infection, avoiding dangers such as necrosis, sepsis, or other fatal hazards.

4. Hemostatic. Hemostasis is the first and very important stage of wound healing because an uncontrolled hemorrhage can lead to death. Fast hemostasis can be achieved with dressings based on hydrogels with a porous structure, which are advantageous because they have excellent capacities for absorbing large amounts of injury exudate and controlling wound bleeding.

5. Supports the growth of skin cells and granulation tissues. Hydrogels are used as carriers for natural compounds or drugs for skin healing. Embedding the drugs or various slow-release bioactive constituents into multifunctional hydrogel scaffolds can lead to an increase in the long-term healing capacity of wounds.

6.2 Delivery of growth factors and cells for tissue skin regeneration

Wound healing is a physiological process that occurs continuously, in several stages: hemostasis, inflammation, proliferation, or formation of granulation tissue, remodeling or maturation of the newly formed tissue [84]. It requires direct dynamic interactions between the extracellular matrix (ECM) and growth factors or indirectly, for example, the binding of different types of cells to the ECM [85, 86]. Growth factors are polypeptide molecules secreted by cells, with a signaling role that adjusts cellular responses corresponding to the stages of healing. During the healing of skin wounds, various growth factors are secreted and released that help synthesize collagen and regenerate the epidermis [87]. The benefits of the administration of growth factors are limited because they have low stability in vivo, slow absorption through the skin, and can be eliminated with the exudate. In clinical practice, the efficient and safe delivery of growth factors requires controlled delivery systems. However, the action time of the growth factors can be increased if they are loaded in natural hydrogel matrices [88]. They have many functional groups that provide suitable binding sites to form stable bonds with growth factors [89].

A promising strategy to regulate skin healing and avoid scar formation after skin injuries involve the use of hydrogel as a pro-regenerative matrix combined with growth factors and different cell types to act directly on local wounds and to stimulate tissue regeneration.

6.3 Clinical applications and case studies

Numerous studies have presented the results of research with the perspective of developing materials for healing wounds with adhesive and hemostatic properties. The research focused on composite hydrogels based on nanoparticles inspired by mussels, recognized for their exceptional ability to adhere in an aqueous environment and for rapid hardening due to the contained Byssus proteins [90]. A very recent study reported the obtaining of a therapeutic and bioinspired hydrogel based on crosslinked CS/COL combinatorial biomacromolecules. Both dry and wet hydrogels obtained incorporated green synthesized AgNPs loaded with cefotaxime sodium. They showed good antimicrobial activity against gram-positive and negative bacteria. Wound healing activity performed on injured rats demonstrated complete wound closure after 2 and 3 weeks, respectively, fully restoring skin function [91]. A novel pharmaceutical hydrogel containing bacteriomimetic microparticles based on membrane vesicles (MV) produced by Lactobacilli was designed for wound healing. The anti-inflammatory effect of the hydrogel was tested on primary human peripheral blood mononuclear cells, and scar formation was observed in a mouse model in vivo. The hydrogel showed anti-inflammatory effects in vitro and a good ability to heal wounds and reduce scar formation in vivo [92].

The fabrication of bioinspired dressings for wounds is of significant interest from the perspective of the increasing incidence of chronic diseases and the increase of resistance to antibiotics. The researchers approached this topic of interest and created hydrogels based on hyaluronic acid methacrylate and gelatin methacrylate, incorporating selenium nanoparticles. The nanoparticles were obtained through a nontoxic microwave-assisted hydrothermal synthesis strategy. The effectiveness of nanoparticle-loaded hydrogels in wound healing was evaluated by the in vitro scratch test. Experiments have shown that nanoparticles significantly improve results compared to other types of nanoparticles, and hydrogels can act as effective dressings to facilitate wound healing [93].

It is known that cardiovascular diseases cause many millions of deaths worldwide every year, and treatments after surgical interventions require the development of new and more effective therapies and medical technology. It is an important direction for top research, and numerous biomaterials-based approaches have extensively investigated this critical area [82]. Open heart operations or heart transplants are major and high-risk interventions, including the risk of infection. Various research has addressed obtaining cardiac patches that provide temporary support to the infarcted area for the administration of cells or bioactive factors or anti-inflammatory drugs. Researchers have developed a novel hydrogel patch for sustained release directly into the infarcted heart to reduce inflammation. The adhesive hydrogel that can be painted was obtained based on dextran-aldehyde (dex-ald) and gelatin, incorporating the anti-inflammatory protein, ANGPTL4. Experiments performed on cardiac tissue treated with ANGPTL4-loaded hydrogel patches showed increased vascularity, reduced inflammatory macrophages, and structural maturation of cardiac cells. In addition, the developed hydrogel showed suitable tissue adhesion, excellent mechanical stability, and sustained release of anti-inflammatory drugs. The results of the in vivo experiments encourage the authors to consider the hydrogel patch a useful tool for the repair of various tissues, including the heart, muscles, and cartilage [94].

The development of biotherapeutic hydrogels offers new treatment options for a wide range of conditions, including acute wounds, diabetic wounds, and burns. The healing process can be affected by many factors, such as bacterial infections, high levels of reactive oxygen species, macrophage dysfunction, sustained hypoxia, excess pro-inflammatory cytokines, age, sex, obesity, diabetes, nutrition, or medication. All these elements are taken into consideration when designing new syntheses of smart hydrogels to provide multifunctional abilities that allow them to effectively respond and accelerate wound healing. Likewise, they can have different properties in real time, such as reactivity to stimuli, injectable self-healing, shape memory, and conductive monitoring [95, 96, 97, 98, 99, 100, 101, 102].

7. Hydrogels in tissue engineering

7.1 Use of hydrogels as scaffolds for tissue regeneration

The potential to coexist and interconnect within specific physiological systems or around tissues without causing damage is the key factor that distinguishes biomaterials from other types of materials. In the modern innovative era, advanced techniques of combining biomimetic materials and incorporating cells and bioactive molecules design tissue engineering scaffolds with distinct 3D structure that ensure mechanical aid for cells in engineered tissues and simulate the native extracellular matrix [1]. The manufacture of biomaterial-based scaffolds that do not induce immune reactions has a decisive contribution in stimulating angiogenic and osteogenic progressions and is based on the selection of the most suitable biomaterial. In the area of tissue engineering, hydrogels based on biomaterials are effective in promoting the healing of bone defects. However, inadequate vascularization in large bone defects is a huge challenge for clinical bioengineering and limits progress in the production of bone substitutes [103].

The biodegradability of the scaffold should be controllable and tunable to allow useful remodeling. This remodeling particularizes vascularization, cellular differentiation, and degradation of the scaffold, so that at the end, this scaffold is substituted by the target tissue [104]. Osteoarthritis is a degenerative disease whose major pathological features are articular cartilage defects, which in turn amplify inflammation in the joint. Cartilage is a significant tissue whose damage can amplify the deterioration of joint function. The tissue’s limited self-repair capacity is insufficient and significant regeneration will not occur due to the complex structure of cartilage, where there are no blood vessels, nerves, or lymphatic tissue. Biomaterials-based hydrogels with elastic structures, with smooth surfaces and a high-water content can be designed with properties adapted for the repair of different types of cartilage defects. Numerous studies have developed and applied advanced hydrogels in vitro or in vivo created for the needs of cartilage tissue engineering and precision medicine.

A very recent study presented the development of a semi-flexible hydrogel that mimics the stiffness of natural tissue and facilitates bone regeneration. The hydrogel based on elastic fibers of reticulated fibrinogen and collagen consumes energy and makes the transition from soft to hard, changing its internal state along with body temperature. Due to its hydrophilicity, the hydrogel quickly adhered to the surface, then became rigid, reducing inflammation in the early stages and contributing to the formation of bone tissue. Due to the ability of accelerated regeneration, this bioinspired hydrogel has the potential to be applied to various other tissues [105].

A new formulation of injectable hydrogel based on kappa-carrageenan-co-N-isopropyl acrylamide (κC-co-NIPAAM) was made by free radical polymerization and antisolvent evaporation technique. The results of digital X-ray investigation using an in vivo bone defect model showed that the synthesized hydrogel improved bone regeneration [106].

Hydrogels serve as supporting matrices to deliver cardiomyocytes and stem cells in regenerating cardiac tissue into infarcted cardiac muscle. Among the hydrogel types used for cardiac tissue are natural polymer hydrogels, synthetic polymer hydrogels, or hybrid hydrogels [107]. Research highlights the hydrogels with elastomeric, conductive, and oxygen-releasing properties and stimuli-responsive hydrogels, which have the ability to react to a range of physical, chemical, and biological stimuli, mimicking the cardiac tissue [108, 109]. Liver tissue engineering projects the development of physiologically applicable liver models. The recent in vitro models of livers made with the help of bioengineering are encouraging for testing drugs, toxicological studies or as disease models and as a possible alternative, in the future, to insufficient donor organs, to treat end-stage liver diseases [110].

7.2 Encapsulation of cells within hydrogel matrices

It is now known that the synergistic interaction between immune cells and cellular encapsulation is responsible for a proper regenerative process, which is the basis of the new concept of modular tissue engineering. Thus, cell-laden hydrogels are being investigated as native-like systems for various applications in regenerative medicine and hard tissue repair. The development of cell encapsulation strategies in different biodegradable hydrogel formulas provides several advantageous features for tissue engineering applications, such as (i) ease of application, (ii) a highly hydrated substrate that provides a favorable environment for cell and tissue growth, (iii) the possibility of it is formed in vivo, and (iv) controlled degradation [111].

Degradation regulation can be achieved by (i) the selection and use of natural biopolymers that are susceptible to enzymatic degradation and (ii) the integration into the hydrogel of segments that are less stable from a hydrolytic or enzymatic point of view. Since the encapsulation of the cells occurs together with the gelation process, the number of suitable formulations is limited.

7.3 Challenges and advancements in tissue engineering with hydrogels

One of the current scientific challenges is the study of the structure of hydrogels derived from the extracellular matrix proteins of natural tissues, the quantification of their composition and their extensive characterization, for their application as injectable or preformed cell delivery matrices in tissue engineering and regenerative medicine.

Protein-based biopolymers obtained from natural tissues have a hierarchical configuration in their native state. They are isolated from their natural tissue through various advanced processes and solubilized in an aqueous solution to be remodeled into injectable or preformed hydrogels for tissue engineering and regenerative applications.

Bio gels are advanced materials based on novel biopolymers derived from proteins, lipids, nucleic acids, and carbohydrates, which provide the bioactive amino acid sequences required for the adhesion, growth, and maturation of encapsulated cells.

8. Hydrogels in ophthalmic and dental applications

The recent applications of hydrogels in ophthalmology highlight their capacity as versatile, efficient, biocompatible, and adaptable therapeutic tools. They prove the ability to target, control, and sustain drug release to the posterior segment of the eye, minimizing invasive operations and improving patient results [112]. Also, hydrogels are useful in postoperative drug delivery and disease detection. However, most hydrogel-based studies remain in preclinical stages, requiring rigorous clinical evaluations [113].

Hydrogels are useful in ocular applications such as soft contact lenses (SCLs) or as materials during contact lens development and can be integrated with nature-inspired drug immobilization and release strategies, providing useful tools for ocular delivery systems of medicines [114].

Oral tissue engineering uses dental biomaterials that require a dual purpose: combating bacterial infections and promoting tissue growth. Biomaterial-based hydrogels demonstrate exceptional potential for oral tissue regeneration and drug delivery [115].

Materials based on hydrogels must face specific challenges, such as the oral environment with sudden temperature changes, the presence of different categories of bacteria, and pH fluctuations caused by saliva and biofilms [116]. Controlled syntheses of hydrogels can regulate their porous structure to achieve pores of the right size and shape with the surrounding tissues, promoting cell adhesion and growth and being useful in regenerative therapy [117, 118].

Among the advantages of hydrogels for oral applications:

• high fluid absorption capacity,

• antibacterial properties,

• effective drug release carriers,

• response to external physical, chemical, and biological stimuli,

• promotes the regeneration of oral tissue.

9. Targeted therapy in theragnostic

Hydrogels are promising tools widely applied in the treatment of cancer by chemotherapy, radiotherapy, immunotherapy, hyperthermia, photodynamic therapy, and photothermal therapy (Figure 2) [119].

Figure 2.

The applications of hydrogels (A) cancer chemotherapy; (B) radiotherapy; (C) immunotherapy; (D) hyperthermia; (E) photodynamic therapy and photothermal therapy [119].

The main advantages of hydrogels as excellent carriers of new drugs in cancer treatment are:

• their use as controlled and precise systems for the continuous and sequential release of drugs, chemotherapeutics, radionuclides, immunosuppressants, hyperthermia agents, phototherapy agents, and other substances.

• targeting different sites and categories of cancer, thus reducing the dose of common drugs, and improving the efficiency of the treatment.

• providing intelligent responses to environmental changes depending on internal and external environmental stimuli, with the possibility of remote control and the release on demand of various active anticancer substances.

• the combination of imaging and therapeutic applications in an only one theragnostic platform by incorporating different contrast agents or nanoparticles in the hydrogel matrix and monitoring in real time the response to the treatment and the stage of the disease.

• the possibility of adjusting the treatment parameters in real time, optimizing the therapeutic results, and minimizing the development of drug resistance and side effects.

As targeted therapy in theragnostic, injectable hydrogels have a huge potential due to the possibility of in vivo application and their distinctive way of administration in the human body. Design strategies aim to develop multifunctional injectable hydrogels with good adhesion, elasticity, and bioresorbability in vivo to be applied via a minimal route. In the structure of the hydrogel, functional bionanomaterials can be incorporated to be used in various diagnostic and therapeutic applications in vivo, including on representative organs such as the skin, liver, heart, and urinary bladder [120].

10. Challenges and future perspectives

Several challenges persist in the field, which researchers are actively addressing to advance the field.

1. Biocompatibility and immunogenicity

Ensuring the biocompatibility of hydrogels is essential for their safe and effective use in biomedical applications. Hydrogel degradation products or residual crosslinking agents may induce inflammatory responses or immune reactions in vivo, limiting their clinical utility.

1. Mechanical properties and stability

Achieving adequate mechanical properties and stability is critical for the structural integrity and functional performance of hydrogels in vivo. Weak mechanical properties or rapid degradation may compromise the longevity and efficacy of hydrogel-based therapies.

1. Control over drug release kinetics

Precise control over drug release kinetics is essential for optimizing therapeutic efficacy and minimizing side effects in drug delivery applications, particularly in complex biological environments.

1. Biomimetic tissue engineering constructs

Fabricating biomimetic tissue engineering scaffolds with appropriate structural and biochemical cues to promote tissue regeneration remains a formidable challenge. Mimicking the complex hierarchical organization and microenvironment of native tissues in hydrogel-based constructs is essential for successful tissue engineering outcomes.

1. Clinical translation and regulatory hurdles

Transitioning hydrogel-based technologies from the laboratory to clinical practice poses significant time, regulatory, and translational challenges. Establishing robust preclinical evaluation protocols, conducting well-designed clinical trials, and addressing manufacturing challenges are critical steps toward successful commercialization and widespread adoption.

1. Therapeutic efficacy and clinical outcomes

Demonstrating the therapeutic efficacy and clinical benefits of hydrogel-based therapies in human patients remains a fundamental challenge. Robust preclinical studies and clinical trials are needed to validate the safety, efficacy, and long-term outcomes of hydrogel-based interventions. Rigorous preclinical evaluation and clinical validation of hydrogel-based therapies are essential for establishing their clinical utility and market acceptance.

10.1 Future trends and potential advancements – emerging technologies in hydrogel research

As researchers continue to push the boundaries of hydrogel technology, several emerging trends and potential advancements are shaping the future landscape of hydrogel research, promising to revolutionize for revolutionizing healthcare and biomedical applications.

10.1.1 Smart hydrogels for precision therapeutics

Smart hydrogels, engineered to respond to specific stimuli such as temperature, pH, light, or biomolecular signals, offer unprecedented control over drug release kinetics and therapeutic delivery. These stimuli-responsive hydrogels enable precise spatiotemporal modulation of drug release tailored to the dynamic physiological microenvironment. From on-demand drug release to triggered responses to disease biomarkers, smart hydrogels offer versatile platforms for precision medicine applications.

10.1.2 3D bioprinting for biomimetic tissue engineering

3D bioprinting technology enables the fabrication of complex, biomimetic tissue engineering constructs with precise spatial control over cell distribution, scaffold architecture, and biochemical cues. By integrating cells, biomaterials, and growth factors into customizable 3D structures, bioprinting holds promise for engineering functional tissues and organs ex vivo, and organ transplantation.

10.1.3 Bioactive hydrogels for regenerative medicine

Bioactive hydrogels, incorporating bioactive molecules, cell-adhesive peptides, and growth factors, mimic the biochemical cues of the native extracellular matrix to promote tissue regeneration and repair. These bioactive cues facilitate cell adhesion, proliferation, and differentiation within hydrogel scaffolds, fostering tissue-specific regeneration. From promoting bone regeneration and cartilage repair to facilitating cardiac tissue engineering and neural regeneration, bioactive hydrogels offer therapeutic interventions for a wide range of degenerative diseases and traumatic injuries.

10.1.4 Nanotechnology-enabled drug delivery systems

Nanotechnology-based drug delivery systems, incorporating nanoparticles, liposomes, or nanofibers within hydrogel matrices, offer precise control over drug loading, release kinetics, and targeting specificity. These nanocomposite hydrogels enable efficient encapsulation and delivery of therapeutic agents, overcoming biological barriers and enhancing therapeutic efficacy.

10.1.5 Multifunctional hydrogels for theragnostic

Multifunctional hydrogels, integrating therapeutic and diagnostic functionalities within a single platform, enable theranostic applications for disease diagnosis, monitoring, and treatment. These theranostic hydrogels combine drug delivery capabilities with imaging modalities, biosensing capabilities, or controlled release mechanisms, offering integrated solutions for precision medicine.

The future of hydrogel research is characterized by transformative advancements and innovative technologies that promise to revolutionize healthcare and biomedical applications. From smart hydrogels for precision therapeutics to 3D bioprinting for biomimetic tissue engineering, bioactive hydrogels for regenerative medicine, nanotechnology-enabled drug delivery systems, and multifunctional hydrogels for theragnostic, the potential for hydrogel-based technologies is vast and far-reaching.

11. Conclusions

Biomaterials-based hydrogels represent a frontier in biomedical engineering, offering versatile platforms for a wide range of therapeutic applications, including drug delivery, tissue engineering, regenerative medicine, and diagnostics. The unique properties of hydrogels, such as biocompatibility, tunable mechanical properties, and controlled release kinetics, make them invaluable tools for addressing complex biomedical challenges and improving patient outcomes. From the design and formulation of hydrogels to the incorporation of therapeutic agents, control over drug release kinetics, and future directions in research and development, biomaterials-based hydrogels offer transformative opportunities for precision medicine and personalized therapy. Hydrogels have demonstrated remarkable potential in targeted drug delivery, enabling localized delivery of therapeutic agents to specific tissues or organs while minimizing systemic toxicity. By engineering stimuli-responsive hydrogels, researchers can achieve precise control over drug release kinetics, enabling on-demand and site-specific delivery tailored to the dynamic physiological microenvironment. Moreover, hydrogels hold promise for tissue engineering and regenerative medicine applications, where they serve as scaffolds for cell encapsulation, proliferation, and differentiation. Bioactive hydrogels, incorporating growth factors, cell-adhesive peptides, and extracellular matrix components, facilitate tissue-specific regeneration and repair, offering therapeutic interventions for degenerative diseases and traumatic injuries. Looking ahead, future advancements in biomaterials-based hydrogel research are expected to focus on smart hydrogels for precision therapeutics, 3D bioprinting for biomimetic tissue engineering, nanotechnology-enabled drug delivery systems, and multifunctional hydrogels for theragnostic. By harnessing the collective expertise of multidisciplinary researchers, engineers, clinicians, and industry partners, we can anticipate continued innovation and translation of hydrogel-based technologies into clinical practice, ultimately improving patient care and quality of life. In conclusion, biomaterials-based hydrogels hold immense promise for therapeutic applications, offering innovative solutions for addressing unmet medical needs and advancing healthcare. As research in hydrogel science and engineering continues to evolve, the potential for biomaterials-based hydrogels to revolutionize medicine and transform the treatment landscape is boundless.

Conflict of interest

The authors declare no conflict of interest.