Three-Dimensional (3D) Printing Scaffold-Based Drug Delivery for Tissue Regeneration

Abstract

Tissue regeneration is essential for wound healing, organ function restoration, and overall patient recovery. Its success significantly impacts medical procedures in fields like internal medicine and orthopedics, enhancing patient quality of life. Recent advances in regenerative medicine, particularly the combination of advanced drug delivery systems (DDS) and bioengineering, have enabled customized methods to improve tissue regeneration outcomes. However, conventional tissue engineering techniques have drawbacks, often using static scaffolds that lack the dynamic properties of real tissues, leading to subpar healing outcomes. The use of 3D printing and other advanced scaffolding techniques allows for the creation of bio functional scaffolds that deliver bioactive molecules at precise locations and times. The optimal integration of biological systems with enhanced material properties for personalized treatment options remains unclear. There is a need for more research into the complex interactions between cellular biology, drug delivery, and material technology to improve tissue regeneration. Despite progress in developing bioactive scaffolds and localized drug delivery methods, the interactions among different scaffold materials, bioactive agents, and cellular behaviors within the regenerative ecosystem are not fully understood. While there is extensive research on 3D-printed scaffolds in tissue engineering, there is a lack of studies integrating bio printing with in vivo biological reactions in real time. Limited research on the dynamic integration of patient-specific parameters in regeneration methods highlights the need for customized approaches that consider individual physiological differences and the complex biological environment at injury sites. Additionally, challenges arise when translating laboratory results into effective therapeutic applications, underscoring the necessity for interdisciplinary collaboration and innovative design approaches that align advanced material properties with biological needs.

1. Introduction

Tissue regeneration, the body’s ability to repair and regenerate damaged or destroyed tissues, is a crucial medical function [1]. This phenomenon has a significant impact on patient recovery and overall health due to its critical involvement in wound healing, injury recovery, and restoring normal organ function following damage [2]. The quality of life for patients is significantly enhanced when tissues are successfully regenerated, restoring their structural integrity and functional capabilities [3]. Developing treatment approaches that can accelerate this natural process requires an understanding of the mechanics underlying tissue regeneration. Orthopedics, skin restoration, and internal organ recovery are a few of its many applications [4]. Even in cases where regeneration is theoretically feasible, conventional methods usually face significant challenges [5,6]. Traditional tissue engineering techniques use static scaffolds, which restricts their bioactivity and makes it impossible to replicate the live, breathing environment of genuine tissues [7]. This results in less than ideal healing outcomes. Targeted therapy is ineffective and raises the risk of systemic side effects due to the lack of specificity and control in conventional pharmaceutical delivery systems [8,9].

The development of scaffolds that can maintain tissue integrity and promote healing by delivering bioactive molecules where and when needed requires innovative strategies that integrate bioengineering and state-of-the-art drug delivery technology [10]. Since scaffolds must mimic the mechanical properties of regenerated tissue, their mechanical properties are crucial. Scaffolds adjusted for mechanical strength can improve cartilage regeneration, and scaffolds tailored to mechanical strengths can significantly increase cellular activity, which in turn promotes tissue regeneration [11]. Vascular systems must be incorporated into the scaffolds for large tissue creations, where waste exchange and supply of nutrients are critical [12]. Scaffolds that promote the development of vascular networks can significantly improve tissue integration and functionality [13]. Vascularized scaffolds are a crucial part of advanced biomaterial design because they facilitate the effective delivery of growth factors and other bioactive materials to certain cells [14]. By incorporating drug delivery mechanisms into scaffolds, medicinal chemicals can be targeted to certain regions, increasing treatment effectiveness and lowering systemic adverse effects [15]. The ability of scaffolds to release drugs in response to external stimuli or when necessary, has the potential to significantly affect patient outcomes. For example, the use of novel dual drug delivery systems (DDS) that allow the targeted release of multiple therapeutic agents is essential to address the complex biological processes involved in tissue regeneration [16].

Recent advancements in regenerative medicine, such as 3D printing, are beginning to address these issues by creating intricate bio functional scaffolds that are specific to each patient. According to Zhao et al. (2020), scaffolds with varying mechanical properties, porosity, and drug-loading capacities may enhance regeneration by enabling the targeted delivery of medicinal agents [17]. New techniques that combine materials science and biological principles have made it possible to achieve better and more reliable functional tissue regeneration. These techniques combine the delivery of drugs with scaffolding [18,19]. This all-encompassing strategy optimizes the healing process and creates new avenues for the creation of customized regenerative medications. DDS are vital to tissue regeneration because they increase the therapeutic efficacy and allow for the functional healing of damaged tissues. DDS are made to release pharmacological substances in a controlled manner, allowing them to enter the desired tissues at the proper concentration for a predetermined period of time. Because it enables a persistent response that complements the body’s natural healing processes, this controlled release is essential in tissue regeneration applications. New approaches, including drug-loaded scaffolds, hydrogel-based systems, and micro- or nano-carriers that can encapsulate a range of bioactive compounds, are being developed to help heal and regenerate injured tissues. These substances include cytokines, growth factors, and anti-inflammatory drugs [20,21].

In order to overcome the drawbacks of systemic therapies which frequently have low bioavailability and a high risk of off-target effects localized drug delivery methods are very important [22]. Traditional delivery methods’ inefficiency for tissue regeneration is frequently caused by their lack of selectivity, which lessens the therapeutic efficacy. Drugs can be efficiently kept at injury sites by employing localized systems, which improves their interaction with extracellular matrix (ECM) and cells that are essential for tissue repair. Through scaffolds that use biodegradable carriers, substances such as vascular endothelial growth factor (VEFG) and bone morphogenetic proteins (BMPs) can be gradually delivered into the body to enhance cellular activities like proliferation, differentiation, and angiogenesis during regeneration. This improved drug delivery specificity solves a major problem in regenerative medicine by optimizing therapeutic results while reducing possible adverse effects [23,24].

Furthermore, there are more chances to improve tissue regeneration when cutting-edge drug delivery technologies are combined with sophisticated materials science. For instance, the development of 3D-printed scaffolds enables the development of DDS that are more individualized and closely resemble the natural architecture of tissues [25]. In addition to aligning the scaffold’s mechanical characteristics with those of the surrounding tissues, this optimization is essential for customizing medication release patterns to meet the demands of each patient. The creation of intelligent DDS that react to environmental cues will improve the accuracy and effectiveness of regenerative techniques as scientists continue to clarify the mechanisms underlying tissue regeneration, ultimately improving patient outcomes [26,27].

The purpose of this review article is to provide an overview and evaluation of current techniques and advancements in tissue regeneration, with an emphasis on the ways in which bioengineered scaffolds, such as novel DDS, and enhance healing outcomes. This review aims to explore the critical role of these advanced scaffolds in improving tissue regeneration processes by addressing the shortcomings of traditional tissue engineering approaches, such as the efficacy of immobile scaffolds and unregulated drug delivery systems. By analyzing significant advancements like nanomaterials and 3D printing technology, this article seeks to provide a thorough overview of how bioengineering and sophisticated medication delivery can enhance patient outcomes in regenerative medicine. It will then demonstrate how these developments might be customized for particular clinical uses in internal organ recovery, skin repair, and orthopedics Additionally, the review will examine the usefulness of drug-loaded scaffolds, evaluating how their capacity to deliver therapeutics locally can enhance cell differentiation and proliferation while reducing systemic side effects frequently associated with conventional drug delivery techniques.

2. 3D Printing Technologies

The biomedical sector is one where additive manufacturing, also known as 3D printing, has revolutionized the field as shown in Figure 1. Stereolithography (SLA), fused deposition modeling (FDM), and bio-printing are three of the most popular methods for printing three-dimensional structures (Table 1).

In FDM, thermoplastic filaments are melted and then extruded in layers to produce 3D objects. The low operating costs and convenience make it useful for tissue engineering’s creation of tailored scaffolds [19,28]. On the other hand, SLA uses a UV laser to layer-cure liquid resin into solids, offering superior resolution and precision. This technique works more precisely than FDM, which makes it perfect for intricate applications such as vascularized tissue models. According to Kim et al. (2017), bio-printing holds great potential for regenerative medicine since it uses living cells throughout the printing process to create intricate tissue-like structures that can support cellular functions [29,30].

When comparing these techniques based on material diversity, scalability, and fabrication speed, notable differences become apparent. Özbolat and Hospodiuk (2016) evaluated that FDM is usually faster than SLA, particularly when working with larger structures. Nevertheless, the resolution of FDM may not meet to SLA for complex designs. Unlike FDM techniques, which can easily be modified to create larger structures, SLA may struggle to scale without compromising print quality because to its lower resolution [31]. Additionally, SLA is often only effective with photopolymers, while improved formulations of photopolymers have expanded SLA’s potential [32]. In contrast, FDM can handle a greater range of thermoplastics. Bio-printing is intrinsically more complex than conventional printing techniques because bio-inks capable of preserving cell viability during printing need to be carefully selected and manufactured [33].

All the strategies have been very beneficial for scaffold-based DDS in the field of tissue regeneration. The versatility of FDM for composite materials allows for the creation of structural scaffolds that enhance mechanical properties and allow for controlled drug release patterns. Özbolat and Hospodiuk (2016) assert that scaffolds intended to support cellular functions and DDS need to be very adaptable [34,35]. Making scaffolds mimic the intricate structure of actual tissues is essential for promoting cellular adhesion and development. This is made possible by SLA’s high resolution. However, the ability of bio-printing to blend various cell types with various materials opens up new possibilities for the creation of complex tissue architectures that can function as drug delivery platforms and replicate the structure of real tissue [36]. One of the primary objectives of 3D printing technology is to enhance drug delivery for tissue regeneration, which is contributing to the growth of the regenerative medicine industry.

Table 1. Comparison of major 3D printing modalities for biomedical and tissue engineering applications, highlighting their printing principles, materials, resolution, scalability, biocompatibility aspects, biomedical uses, and translational/regulatory considerations.

Modality	Principle	Materials	Resolution	Scalability	Biocompatibility/Bioactivity	Applications	Regulatory Considerations	Ref
FDM (Fused Deposition Modeling)	Extrusion of melted thermoplastics layer by layer	Thermoplastics, composites	Moderate (micron to sub-mm)	High; suitable for large scaffolds	Biocompatible options; supports drug delivery; post-processing effects	Structural and bone/dental scaffolds; drug-delivery systems	GMP-ready; wide material range; use of certified thermoplastics	[37]
SLA (Stereolithography)	Photopolymerization of resin using UV light	Photopolymers; bioresins	High (sub-10 μm to tens of μm)	Moderate; limited by vat size	Biocompatible resins; requires thorough post-curing	Intricate scaffolds; vascularized tissue models	Focus on resin safety; leachable control; formulation-based	[38]
Bio-printing (3D Bioprinting)	Layered deposition of living cells and bioinks	Bioinks (cell-laden hydrogels)	Variable; micro-scale possible	Moderate; limited by cell viability	Promotes adhesion, differentiation, vascularization	Tissue constructs; organ patches; models	Complex regulation; GMP and sterility critical; long approval time	[39]

Table 1. Comparison of major 3D printing modalities for biomedical and tissue engineering applications, highlighting their printing principles, materials, resolution, scalability, biocompatibility aspects, biomedical uses, and translational/regulatory considerations.

Modality	Principle	Materials	Resolution	Scalability	Biocompatibility/Bioactivity	Applications	Regulatory Considerations	Ref
FDM (Fused Deposition Modeling)	Extrusion of melted thermoplastics layer by layer	Thermoplastics, composites	Moderate (micron to sub-mm)	High; suitable for large scaffolds	Biocompatible options; supports drug delivery; post-processing effects	Structural and bone/dental scaffolds; drug-delivery systems	GMP-ready; wide material range; use of certified thermoplastics	[37]
SLA (Stereolithography)	Photopolymerization of resin using UV light	Photopolymers; bioresins	High (sub-10 μm to tens of μm)	Moderate; limited by vat size	Biocompatible resins; requires thorough post-curing	Intricate scaffolds; vascularized tissue models	Focus on resin safety; leachable control; formulation-based	[38]
Bio-printing (3D Bioprinting)	Layered deposition of living cells and bioinks	Bioinks (cell-laden hydrogels)	Variable; micro-scale possible	Moderate; limited by cell viability	Promotes adhesion, differentiation, vascularization	Tissue constructs; organ patches; models	Complex regulation; GMP and sterility critical; long approval time	[39]

2.1. Scaffold Architecture and Drug Delivery Optimization

Optimizing DDS is essential for ensuring targeted administration of bioactive compounds, lowering systemic side effects, and increasing therapy effectiveness [40,41]. Scaffold architecture has emerged as a crucial component of the many DDS approaches (Figure 2). Therapeutic substances can be incorporated into 3D scaffolds in various innovative ways that maximize drug delivery without compromising the scaffold’s structural integrity [42]. One effective method is post-fabrication drug impregnation, which involves infusing medications into scaffolds after their initial construction, as noted by Ahangar et al. (2023) [43]. This approach enables controlled therapeutic release properties [43]. Another method involves combining the drugs with the polymer matrix during the scaffold manufacturing process, allowing for uniform dispersion of the medications throughout the material. Additionally, drug-loaded polymers can be directly extruded using the 3D printing technique, enhancing the integration of drug release patterns with the scaffold’s structural properties. This simultaneous production and injection of medicinal compounds is another advantage of this approach [44]. A novel strategy involves using a dual-material system that combines structural scaffolds with drug-containing gels, which improves the scaffold’s mechanical stability and functional effectiveness. This method allows for localized drug administration over an extended period [45]. These diverse techniques highlight the potential and versatility of 3D printing technology in developing improved drug delivery systems for regenerative medicine [46].

A scaffold is a 3D matrix that promotes cell proliferation, aids in drug release, and functions similarly to the ECM in tissues [47,48]. The choice of scaffold architecture has a significant impact on the therapeutic efficacy, cellular interactions, and drug release kinetics of specific medications [49,50]. It is crucial to consider biocompatibility, mechanical stability, biodegradability, and porosity while building a scaffold. In biological contexts, fluid movement is crucial for waste removal and nutrient exchange, and scaffolds with high porosity boost drug loading surface area. Scaffolds derived from natural sources, such as collagen, alginate, or chitosan, are highly biocompatible and bioactive. For instance, scaffolds composed of gelatin, a denatured form of collagen, can help carry medications while promoting cell adhesion and proliferation [51].

They are composed of polyglycolic acid (PGA), polycaprolactone (PCL), and polylactic acid (PLA), which are polymers [27,52]. On synthetic scaffolds, mechanical properties and degradation rates can be altered, however surface modification could be required to increase biocompatibility. Through functionalization, the scaffold–cell interface can be enhanced or drug affinity raised [53,54]. For example, by adding specific ligands or peptides, the scaffold can be altered to improve cell adhesion or elicit specific biological reactions. Stimuli-responsive polymers can be used to produce controlled medication release profiles by changing their properties in response to environmental stimuli, such as variations in pH or temperature, which can help cure localized diseases even more.

2.2. Optimization of Drug Delivery

Optimizing drug delivery with scaffold architecture requires careful consideration of the scaffold’s design, the phytochemicals that are contained, and methods for achieving controlled release [55]. Common methods for encapsulating drugs in scaffolds include phase separation, chemical casting, and electrospinning. Each of these techniques can be used to regulate the rate of drug release and bioavailability [56]. Phytochemicals like gingerol and curcumin require effective delivery mechanisms to realize their antioxidant and therapeutic potential due to their low bioavailability. The rate at which drugs are released from scaffolds can be regulated in a number of ways such as, drug diffusion through the scaffold matrix is influenced by pore size and geometry, which in turn affects release rates. Scaffolds with larger pore sizes tend to enhance drug release more quickly. In this instance, the degradation of the scaffold material regulates the release of medication. Biodegradable scaffolds’ rates of breakdown can be adjusted to match the medication’s intended therapeutic impact [57].

2.3. Printing Modalities

FDM is the preferred technique for thermoplastic drug-delivery matrices and structural scaffolds because of its versatility, speed, and ease of use [58]. Quick extrusion and layer-by-layer construction make it economical to create larger, patient-specific scaffolds with adjustable mechanical and porosity characteristics. These characteristics are essential for staged medication release and load-bearing applications. FDM frequently offers lower resolution than SLA, which is one of the main reasons SLA is still the best option for intricate designs that require high-resolution details [59]. Delicate tissue microarchitectures and vascular networks may become more difficult to duplicate as a result [60]. Layer-wise photopolymerization in SLA allows for the creation of complex shapes with greater precision and resolution. This is particularly helpful for fine-featured scaffolds and vascularized tissue models. SLA’s photopolymer resins can produce surface features and complex pore architectures that promote cellular adhesion and organization when they are biocompatible and properly prepared [61,62]. New advances in photopolymer formulations and post-processing are creating intriguing opportunities for biological scaffolds manufactured using SLA, even though SLA can only use photopolymers and that scaling prints without compromising quality is still a constant effort [63].

Using living cells and bioinks, referred to as 3D bio printing makes it possible to create structures that resemble biological tissue [64]. In order to guarantee cell survival and biocompatibility, hydrogels which mimic ECM cues are commonly added to bio-inks. Rheological properties are then matched for printability. Intricate tissue structures and the potential for in situ tissue regeneration are made possible by the use of living cells in bio printing; nevertheless, process control, sterility, and regulatory concerns all become additional difficulties [65]. A synthesis of multiple modalities reveals complementary strengths and appropriate application niches [66,67,68]. Three-dimensional printing offers high-fidelity, detailed geometries appropriate for microvascular networks and tissue interfaces; bio-printing enables the incorporation of cells and bioactive components to recapitulate tissue physiology and facilitate cell-guided regeneration; and FDM offers quick, scalable production of sturdy scaffolds and drug-delivery matrices with a wide range of material options [69]. The literature strongly recommends a hybrid or sequential method when appropriate; for example, printing hard scaffolds or vasculature from FDM or SLA, then adding bioinks or seeding cells on top to generate functional tissues [70].

Thermoplastics and composites, which enable tunable mechanical properties and degradation profiles, are used to create the fundamental FDM scaffolds [71,72]. These characteristics allow for regulated medication release and can be modified to match target tissues. The ability to mimic the mechanical environment of native tissues and tailor drug release kinetics is a key component of scaffold-based therapy and regenerative medicine. FDM’s adaptability to composite materials made it possible [73]. When choosing and creating photopolymers for SLA, biocompatibility, printability, and compatibility with live tissues during post-processing are important factors to take into account. The shift to surface-functionalized materials and biocompatible photopolymers aims to improve integration with host tissues and decrease immunological responses. This change complies with Good Manufacturing Practices (GMP) requirements for clinical translation as well as regulatory expectations [74].

Hydrogel-based cell-laden inks offer environments akin to the ECM, which support cell growth, survival, and differentiation. The cell–material interface, which encompasses hydrogel mechanics, biochemical signaling, and crosslinking techniques, governs cell fate and the development of functional tissue. In order to increase biocompatibility and develop processable materials that mimic tissue ECM, research is being conducted on plant-based fibers, natural gums, and other polymers and composites [75]. Using natural composites in 3D printing is thought to improve mechanical characteristics, biocompatibility, and environmental sustainability, despite the fact that study on scalability and interfacial compatibility is still needed [76]. According to a cross-cutting conclusion about materials, the majority of therapeutically successful solutions often include bioactive components and multi-material integration [77]. While FDM and SLA provide the structural and micro architectural foundation, bio-inks and hydrogels bring live components and signaling environments to the table, enabling tissue growth and differentiation [78].

2.4. Application in Drug Administration and Regenerative Medicine

The controlled release of medications via scaffolds is a common objective; SLA excels at creating microarchitectures that can influence diffusion and cellular exposure, while FDM excels at creating porous, mechanically robust scaffolds [79]. By enabling the spatial distribution of drugs within a tissue-mimicking matrix or by incorporating drug-loaded nanoparticles within bioinks, bio-printing creates new opportunities for localized drug delivery in regenerating tissues [80]. In the field of tooth and periodontal regeneration, 3D printing has demonstrated the ability to reconstruct complex organ systems, including the periodontium and supporting bone, using bioengineered scaffolds and, increasingly, bioprinted tissues. Combining living cells with high-resolution scaffolds can replicate native shape and function, which may be helpful for dental applications like medication administration and regeneration [81].

Vascularized tissue engineering and organ-level structures are becoming increasingly possible as bio-inks, stem-cell printing, and microvascular network manufacturing technologies advance. Using a specialized decellularized ECM (d ECM) bioink, we developed a bioprinting technique, as depicted in Figure 3 and Figure 4, to create cell-filled structures. This technology provides an ideal environment for the growth of 3D organized tissue, enabling the restoration of natural cell morphologies and functions. This bioprinting technique found to be versatile and effective, utilizing a variety of d ECM bioinks, including those derived from heart, cartilage, and adipose tissues. The functional cell-printed structures exhibited tissue-specific gene expression and complex spatial patterns, indicating higher-order assembly and potential applications [82].

The accuracy of SLA and the versatility of FDM, along with bio-inks to incorporate essential biological components, make these systems advantageous, but the regulatory pathways for these devices must be thoroughly examined. Research generally agrees that the practical translation of additive manufacturing (AM)-based tissue engineering and bio printing requires enhanced materials with shown biocompatibility, robust production controls that meet GMP requirements, and a synergistic use of modalities [83]. Material-functionalization techniques, immune-system-compatible bio-inks, and standardized procedures for printing, post-processing, and sterilizing are necessary to secure regulatory approval and guarantee reproducibility in labs and clinics [84]. The field has realized the value of interdisciplinary collaboration between engineering, materials science, biology, chemistry, and medicine in addressing issues such as scaffold integration, functional tissue development, and living system complexity [85]. Regenerative success depends on vascularization, controlled drug delivery through carefully crafted structures and bioactive signals, and the replication of native ECM. In order to create vascularized, complicated organs and tissues that can take medication, integrated, multi-material techniques that combine the precision of SLA, the scalability of FDM, and the biological sophistication of bio-printing provide the best chances for the future of regenerative medicine [86].

3. Materials for 3D Printing Scaffolds

The advancements in 3D printing technology have significantly expanded the materials available for creating scaffolds for tissue regeneration [87]. Biocompatible materials are essential for scaffold safety and effectiveness because they must permit cell attachment, proliferation, and differentiation while minimizing negative physiological consequences (Table 2). In addition to guaranteeing biocompatibility, it is essential to include biodegradable and bioactive components in scaffold construction [88]. By progressively dissolving and being replaced by freshly formed tissue, scaffolds composed of biodegradable materials might enhance tissue integration and lessen the need for surgical removal. This feature is crucial for applications such as bone regeneration since the scaffold must promote tissue growth while gradually transmitting load until the tissue is able to meet its own physiological needs [9]. However, by encouraging specific cellular reactions, bioactive substances improve tissue regeneration. One of the major problems in tissue engineering is the creation of a vascular supply to the newly produced tissues. Materials that release growth factors or angiogenic signals, for instance, can promote cell migration and vascularization [89].

Because tissue engineering is always evolving, the particular requirements of the application must be taken into consideration while choosing materials. It is becoming more and more evident from continuing research that combining multi-functional traits into a single scaffold can significantly improve therapeutic outcomes [90]. For example, scaffolds that combine the bioactivity of natural materials with the structural integrity of synthetic polymers are being developed to create hybrids that can deliver bioactive agents at the injury site and provide mechanical support. Improved control over the release kinetics of medicinal drugs is made possible by the increased feasibility of customizing scaffold design and material composition with the development of 3D printing technology. Common materials for 3D-printed scaffolds include ceramics, hydrogels, and polymers; each has pros and cons that make it a good choice for certain tissue engineering applications [91].

3.1. Hydrogels

Hydrogels have garnered a lot of attention in the biomedical sector due to their biocompatibility, adaptability, and ability to serve as 3D scaffolds for a range of applications, including tissue formation and medication administration [92]. The use of hydrogels in 3D scaffold designs is a significant advancement in creating artificial environments that support tissue regeneration, cell proliferation, and differentiation. A crucial characteristic of any material utilized in a biomedical context is hydrogels’ high compatibility with living things [93]. By promoting cell adhesion and nutrient exchange, hydrogels which can be composed of natural or synthetic polymers can mimic the circumstances found in real tissues [94]. As biodegradable hydrogels can be designed to degrade at regulated rates, new tissue can take its place as the healing process advances.

The mechanical properties of hydrogels can be altered by varying the cross-linking density, polymer composition, and the addition of nanoparticles or other additives [95]. These changes enable the scaffolds to adapt to their mechanical properties, regardless of whether the goal is a more solid structure like bone or softer tissue [96]. For instance, peptide directed self-assembly techniques can be used to create nanofibrous hydrogels, which enhance the scaffolds’ mechanical strength and in vivo performance [97,98]. In order to maintain a hydrated environment that is conducive to cellular functions and drug diffusion, hydrogels use their swelling behavior as a drug delivery method. Hydrophilic and hydrophobic components must be formulated in a way that manipulates swelling properties in order to control the release rates of encapsulated medications [99,100].

Hydrogels facilitate biological activities and offer structural support, they are crucial components in tissue engineering [101]. By seeding them with stem cells or other suitable cell types, they can be used to repair many tissues, including skin, cartilage, and bones [102,103]. By producing hydrogel scaffolds that closely resemble the complex structure of natural tissues, 3D bio printing and other state-of-the-art methods have significantly increased the success rate of tissue engineering [104]. Due to their versatility, hydrogels can be used to administer medications in a controlled manner. The swelling behavior and porous structure of hydrogels, permits the management of therapeutic agent release over time, can result in improved local drug concentrations and reduced systemic exposure [105]. Researchers have created injectable silk-hydrogel scaffolds to administer chemotherapy medications in a sustained manner, limiting side effects while efficiently targeting tumor cells [106].

Hydrogels are essential in regenerative medicine because they can be used to create environments that support cell survival and the formation of functional tissue [107]. Biomimetic hydrogels can be made to dynamically interact with living cells, altering their characteristics based on the environment within the cells. This responsiveness opens the prospect of developing smart scaffolds that can improve tissue repair mechanisms by releasing growth factors or drugs when needed [108]. The incorporation of 3D printing technology has fundamentally changed the process of producing hydrogel scaffolds. The scaffold design, which includes pore size, shape, and interconnectivity, must be precisely controlled to enhance nutrient flow and cell motility. This is made possible by methods like extrusion and inkjet printing [109]. The development of hybrid scaffolds that combine the benefits of diverse materials is made possible by the capacity to include multiple materials via 3D printing [110].

Method that has shown promise in recreating the structural characteristics of native ECM is electrospinning, which enables the production of nanofibrous hydrogel scaffolds. These scaffolds are well-suited for use in tissue engineering due to their improved mechanical characteristics and increased cellular responses. A new family of materials called self-healing hydrogels has just been developed. These gels can mend themselves when damaged. The capacity to withstand mechanical stress is particularly useful in living organisms that are constantly changing. Hydrogel scaffolds can be made more durable and useful for tissue regeneration by adding self-healing characteristics to them.

3.2. Polymers

Polymers such as PCL and PLA have drawn a lot of interest recently as possible tissue engineering materials [111]. They are interesting candidates for use in 3D scaffolds intended to promote cellular activity and tissue regeneration because of their biocompatibility, special mechanical properties, and ease of fabrication [112]. PLA is a biodegradable thermoplastic made from corn starch and other renewable materials. It is ideal for use in load-bearing applications, including scaffolds in bone tissue engineering, which need to tolerate mechanical stresses similar to those in normal bone, due to its high modulus and tensile strength [113]. The mechanical properties and breakdown rate can be precisely controlled due to its modifiable molecular weight of PLA. The extensive processing capabilities make it simple to shape and incorporate into other production processes, such as electrospinning and 3D printing. This makes it possible to create intricate scaffold designs that closely mimic biological tissue architecture [114].

PCL, a biodegradable aliphatic polyester, may be advantageous because it degrades more slowly than PLA for tissue healing. Due of its low glass transition temperature and flexibility, PCL’s mechanical properties are very beneficial for soft tissue applications [115]. This is particularly true in areas like cartilage repair and vascular grafts. Because PCL is easy to process, it can be mixed with other bioceramics and polymers to create composite scaffolds that increase cellular response and promote healing [116]. Lee et al. developed 3D-printed PCL scaffolds for knee meniscus development that were precisely measured to match the original meniscus. Polymeric microspheres positioned at specific locations on these scaffolds progressively released transforming growth factor-β3 (TGF-β3) and connective tissue growth factor (CTGF). By regulating the spatial and temporal release of proteins, zone-specific matrix formation was made possible, just like in the natural meniscus. As a result, type I collagen developed in the outside zone and type II collagen in the inner zone. Tissue regeneration with the necessary mechanical properties was accomplished in an in vivo model [117].

It is possible to modify the mechanical strength and rate of degradation of poly (lactic-co-glycolic acid) (PLGA), a copolymer that blends PLA and PCL. PLGA is widely used in DDS because to its superior release kinetic control. Gelatin is a biocompatible, naturally occurring polymer that promotes cell adhesion. Hydrogels that imitate the ECM, made possible by its coupling with synthetic polymers such as PCL, are perfect for regenerating skin and organs. Crustacean shells contain a biopolymer called chitosan, which has antibacterial properties and aids in wound healing. The combination with synthetic polymers makes scaffolds more bioactive and stronger mechanically.

The mechanical compatibility and osteogenic differentiation promotion of PLA and PCL in stem cells have led to their substantial investigation in bone tissue engineering [118]. Osteointegration and bone regeneration are greatly improved when PCL scaffolds are combined with hydroxyapatite (HA) or other bioactive ceramics. Biodegradable scaffolds that can be engineered to secrete osteogenic factors to promote targeted healing of bone deformities are being developed with the help of PLA. Soft tissue applications, such cartilage repair, are made possible by PCL’s mechanical characteristics [119]. Chondrogenic differentiation can be supported by PCL scaffolds, which are able to resist the mechanical forces found in joints. The use of natural polymers such as gelatin in conjunction with PCL has also demonstrated great potential for soft tissue repair due to its ability to improve biocompatibility and direct cell behavior via improved surface contacts [120]. Because of their capacity to encapsulate bioactive molecules and enable regulated release, PLA and PCL are particularly versatile as drug delivery platforms. Their processing skills make it possible to create scaffolds that can release therapeutic compounds over long periods of time [121]. This makes them perfect for illnesses like cancer treatments or chronic disease management when sustained release is essential. Novel on-demand drug release methods have reportedly been developed using composite scaffolds that combine PCL with magnetic nanoparticles [122].

Table 2. Material for 3D printing scaffold.

Property	Type	Source	Biocompatibility	Tensile Strength	Processing	Degradation	Applications	Advantages	Composite Use	Ref
Polylactic acid (PLA)	Biodegradable thermoplastic	Corn starch (renewable)	Excellent	High	Easy; 3D printing, electrospinning	Controlled; lactic acid	Bone scaffolds	Strong, customizable	With ceramics (bone)	[123]
Polycaprolactone (PCL)	Biodegradable polyester	Synthetic	Excellent	Moderate	Simple; blindable	Slow	Soft tissue, grafts	Flexible, soft tissue use	Healing composites	[124]
Poly (lactic-co-glycolic acid) (PLGA)	Copolymer of PLA & PCL	Synthetic copolymer	Good	Adjustable	Adjustable; drug delivery	Tunable (PLA/Gly ratio)	Drug delivery, scaffolds	Controlled release	Strengthens delivery systems	[125]
Gelatin	Natural collagen polymer	Animal tissues	Excellent	Variable	Cross-linkable; blindable	Biodegradable	Skin/organ regeneration	Promotes adhesion	With synthetics for ECM	[126]
Chitosan	Biopolymer from chitin	Crustacean shells	Good	Moderate	Blindable; modifiable	Biodegradable; healing aid	Wound healing, antibacterial	Antibacterial, healing	With synthetics for scaffolds	[127]

Table 2. Material for 3D printing scaffold.

Property	Type	Source	Biocompatibility	Tensile Strength	Processing	Degradation	Applications	Advantages	Composite Use	Ref
Polylactic acid (PLA)	Biodegradable thermoplastic	Corn starch (renewable)	Excellent	High	Easy; 3D printing, electrospinning	Controlled; lactic acid	Bone scaffolds	Strong, customizable	With ceramics (bone)	[123]
Polycaprolactone (PCL)	Biodegradable polyester	Synthetic	Excellent	Moderate	Simple; blindable	Slow	Soft tissue, grafts	Flexible, soft tissue use	Healing composites	[124]
Poly (lactic-co-glycolic acid) (PLGA)	Copolymer of PLA & PCL	Synthetic copolymer	Good	Adjustable	Adjustable; drug delivery	Tunable (PLA/Gly ratio)	Drug delivery, scaffolds	Controlled release	Strengthens delivery systems	[125]
Gelatin	Natural collagen polymer	Animal tissues	Excellent	Variable	Cross-linkable; blindable	Biodegradable	Skin/organ regeneration	Promotes adhesion	With synthetics for ECM	[126]
Chitosan	Biopolymer from chitin	Crustacean shells	Good	Moderate	Blindable; modifiable	Biodegradable; healing aid	Wound healing, antibacterial	Antibacterial, healing	With synthetics for scaffolds	[127]

3.3. Ceramics

The bone tissue engineering community has focused a lot of emphasis on ceramics’ osteo-conductive properties, which are essential for effective bone regeneration (Table 3). Calcium phosphate ceramics, such as HA and tri-calcium phosphate (TCP), are distinguished from the others by their composition and functional resemblance to genuine bone material [128]. The various applications of calcium phosphate ceramics in tissue engineering are examined in this section, along with their unique characteristics, particular applications, and methods of promoting cellular activity and regeneration. Because of their special ability to support the growth and attachment of bone-forming cells, scaffolds composed of calcium phosphate ceramics are extremely effective in tissue engineering [129]. Their osteo-conductive nature, which increases bioactivity and promotes bone tissue integration, is caused by their structural similarity to bone mineral components. A major bone component, HA is a solid form of calcium appetite that is non-toxic and biocompatible, it is frequently used for bone repair. The osteo-conductivity enabled by HA scaffolds enables osteoblast adhesion, proliferation, and differentiation, all of which are critical to the processes of bone repair. Studies have shown that HA, when employed as a scaffold, encourages the deposition of bone matrix, producing encouraging results in vivo for applications involving bone repair [130].

TCP, more especially its beta form (β-TCP), is a form of biodegradable calcium phosphate ceramic that is highly resorbable in living things [131]. Its capacity to dissolve and liberate calcium and phosphate ions is essential to the mineralization processes involved in bone repair [132]. Because of their porous shape, which permits cells to penetrate and bones to form, TCP scaffolds are ideal for enhancing osteogenic responses when combined with composite scaffolds. Biphasic calcium phosphate (BCP) ceramics, a combination of HA and TCP, are a desirable alternative for use as bone tissue scaffolds due to their controlled resorption and mechanical robustness. Research indicates that BCP scaffolds enhance osteo-conductive behavior and bone resorption due to the combined effects of the two stages. Studies showing enhanced cell adhesion and differentiation on BCP scaffolds in comparison to pure HA or TCP suggest that BCP may be useful for a variety of orthopedic and craniofacial applications. In these investigations, human mesenchymal stem cells (hMSCs) were used [133].

Calcium silicates are well-known for their bioactivity, but they also have properties that aid osteo conduction. Scaffolds built with strontium-substituted calcium silicate have shown improved cellular connections and the potential for greater tissue growth [134]. By controlling ion release, which in turn stimulates osteogenic differentiation, calcium silicates aid in bone repair. In order to combine mechanical strength and biological function, composite scaffolds have been designed to blend calcium phosphate ceramics with biodegradable polymers such as poly (lactic acid) (PLA) or PCL. These composites can provide the structural support required for bone scaffolding and allow for a tailored degradation rate to match tissue regeneration, therefore improving tissue engineering methods overall. Calcium phosphate ceramics are widely used in bone tissue engineering due to their ability to stimulate bone ingrowth and regeneration at critical defect sites. When seeded with bone marrow-derived stem cells, porous calcium phosphate scaffolds have been demonstrated to support osteogenic differentiation and long-term bone formation. Among the disorders that have responded effectively to their treatment include nonunion fractures and significant bone abnormalities. Recent advancements in additive manufacturing have made it possible to precisely manufacture calcium phosphate-based scaffolds using 3D printing, which can then be tailored to satisfy certain therapeutic requirements. These scaffolds can encourage vascularization, cell proliferation, and nutrient flow in the tissues they form in addition to providing mechanical support. Calcium phosphate ceramics are excellent options for drug administration in bone tissue engineering due to their ability to encapsulate bioactive substances. In situations involving bone regeneration, the regulated release of growth factors like BMP-2 (Bone Morphogenetic Protein-2) from calcium phosphate scaffolds can promote osteogenic differentiation and speed up the healing process [47,85]. Natural polymers like collagen or gelatin can be combined with calcium phosphate ceramics to create hybrid scaffolds with enhanced biological properties. These scaffolds are perfect for soft tissue regeneration applications because they preserve osteo-conductivity while encouraging cell adhesion and proliferation. Collagen-HA composites, for example, have demonstrated encouraging outcomes in bone graft substitutes because of their bioactivity and adjustable mechanical characteristics [135]. Because of their osteo-conductive properties, biocompatibility, and structural resemblance to genuine bone, calcium phosphate ceramics are a crucial part of bone tissue engineering. Innovations in scaffold design and composite formulations are anticipated to improve the effectiveness of calcium phosphates in stimulating bone regeneration as this field of study develops, providing fresh approaches to treating clinical issues related to bone deformities and injuries.

3.4. Hybrid Materials

The incorporation of hybrid materials into scaffold designs has been a significant advancement in the development of 3D-printed scaffolds. Better mechanical properties and biological interactions are made possible, necessary for tissue engineering applications to be effective [136]. Hybrid scaffolds, which combine manufacturing techniques like electrospinning and 3D printing, have higher structural integrity and may support biological performance [137].

One element of a hybrid scaffold that improves mechanical strength and biological reactions is aligned nanofibers [138]. Chen et al. (2022) showed that the addition of electrospun fibers to 3D-printed scaffolds results in a structure that effectively mimics the ECM [139]. This combination strengthens the scaffold and enhances cellular adhesion and proliferation, which is crucial for musculoskeletal tissue engineering applications [139]. Another example is the application of hybrid electrospun mats in conjunction with 3D-printed scaffolding, which expands the surface area available for nutrition transfer and cell penetration [140]. In addition to their mechanical benefits, hybrid materials enable medication administration management, which is critical for scaffold effectiveness [141]. Bioactive glass and alginate scaffolds have demonstrated remarkable efficacy in this field [142]. For instance, Fu et al. (2019) described multilayer scaffolds composed of sodium alginate and mesoporous bioactive glass to facilitate dual-drug release behaviors [143]. As, sodium alginate enhances the printing qualities of the composite and raises the hydrophilicity and porosity of scaffolds, which in turn enable a rapid release of medications, it is a crucial component in bone tissue engineering for targeted therapies [144].

By including bioactive substances that can initiate certain biological responses, hybrid materials also enable improved bioactivity [145]. Mouriño et al. (2011) highlight the advantages of adding bioactive glass nanoparticles to crosslinked alginate films [146]. This technique encouraged biological processes like osteogenesis and improved mechanical properties [146]. By supplying the essential ions that mimic the natural bone environment, the use of these nanoparticles can improve the ability of scaffolds to support tissue regeneration [147]. New advancements in scaffold design have revealed that hybrid systems can enable customizable medication release profiles [148]. Zhou et al. (2017) examined the use of biomaterials based on mesoporous bioactive glass as a way to direct vascularization in the context of bone regeneration [149]. Along with promoting the controlled release of growth factors and signaling molecules, the scaffold also promotes cellular adhesion and proliferation; these actions work in concert to significantly impact the integration and healing processes [150].

3.5. Composite Materials

The development of composite materials that blend natural and synthetic polymers is a key strategy for enhancing the bioactivity and mechanical durability of 3D-printed scaffolds [151]. By utilizing the greatest qualities of each component, these composites create robust scaffolds that support the biological processes required for tissue regeneration [152]. The mechanical properties of PLA and the bioactive properties of HA work together to produce a composite scaffold that has a synergistic effect [153]. Bernardo et al. (2022) demonstrated that their 3D-printed PLA/HA scaffolds significantly improved the osteogenic growth of human mesenchymal stem cells even in the absence of external osteogenic stimuli [154]. It suggests that even in the absence of additional growth hormones, the composite scaffolds may produce an environment that is comparable to that of actual bones, which enhances cell activity and promotes bone regeneration [155]. Similarly, Gregor et al. (2017) clarified the features and layout of PLA scaffolds that were utilized to replace bone tissue [156].

Additionally, Söhling et al. (2022) investigated the possibility of using a PLA composite that contains 20% bioglass for high-resolution scaffold 3D printing [157]. Since it enabled complex internal design and provided the required mechanical strength, their findings confirmed the significance of these biocomposite scaffolds’ structural integrity for bone tissue production [157]. Bioactivity is improved by this combination, which is essential for effective bone repair [158]. The mechanical limits of synthetic polymers, such PLA and HA, which are commonly characterized by brittleness and low load-bearing capacities, can be decreased by adding fillers or modifiers to the composite material [159]. Hlushchenko et al. (2023) emphasize the importance of creating polymer composites with plasticizers and stiff fillers to enhance the mechanical properties required for bone load-bearing applications [160]. This is crucial because scaffolds intended for load-bearing applications in bone tissue engineering need to have extraordinary mechanical strength [160].

Furthermore, recent discoveries in materials science demonstrate that molecular-level modifications can be made to the properties of composites [161]. The difficulties of creating hybrid scaffolds where nanoscale mechanobiology influences stem cell behavior are examined in a work by Naderer et al. (2025) [162]. By adjusting the scaffold’s design and material composition to create environments that promote specific cellular responses, scientists can gain a better understanding of how material properties influence biological outcomes. Using composite materials to create 3D-printed scaffolds is one possible method to enhance biological functionality and mechanical performance [163].

Table 3. Properties of calcium-based biomaterials for bone tissue engineering and regeneration applications.

Material	Osteoconductivity	Biocompatibility	Resorption Rate	Applications	Ref
Hydroxyapatite (HA)	High; supports osteoblast adhesion and proliferation	Excellent; non-toxic and widely used	Slow; ideal for long-term scaffolding	Bone repair, dental applications	[164]
Tricalcium Phosphate (TCP)	High; promotes mineralization	Excellent; well-tolerated in vivo	Fast; biodegradable, releases ions quickly	Bone regeneration, critical defect sites	[165]
Biphasic Calcium Phosphate (BCP)	Enhanced due to combined HA/TCP properties	Excellent; effective for bone repair	Controlled; allows modulation of properties	Orthopedic and craniofacial applications	[166]
Calcium Silicate Ceramics	Moderate; supports cell activity	Good; widely used in dental applications	Variable; depends on composition	Bone and dental regeneration	[167]
Calcium Phosphate Ceramics	High; supports bone cell attachment and growth	Generally high; formulation-dependent	Variable; unable to application	Bone grafting, tissue engineering scaffolds	[168]

Table 3. Properties of calcium-based biomaterials for bone tissue engineering and regeneration applications.

Material	Osteoconductivity	Biocompatibility	Resorption Rate	Applications	Ref
Hydroxyapatite (HA)	High; supports osteoblast adhesion and proliferation	Excellent; non-toxic and widely used	Slow; ideal for long-term scaffolding	Bone repair, dental applications	[164]
Tricalcium Phosphate (TCP)	High; promotes mineralization	Excellent; well-tolerated in vivo	Fast; biodegradable, releases ions quickly	Bone regeneration, critical defect sites	[165]
Biphasic Calcium Phosphate (BCP)	Enhanced due to combined HA/TCP properties	Excellent; effective for bone repair	Controlled; allows modulation of properties	Orthopedic and craniofacial applications	[166]
Calcium Silicate Ceramics	Moderate; supports cell activity	Good; widely used in dental applications	Variable; depends on composition	Bone and dental regeneration	[167]
Calcium Phosphate Ceramics	High; supports bone cell attachment and growth	Generally high; formulation-dependent	Variable; unable to application	Bone grafting, tissue engineering scaffolds	[168]

4. Scaffold Design for Drug Delivery

In order to promote healing and restore functioning tissue, drug delivery scaffolds for tissue regeneration must be structurally engineered. These scaffolds not only provide structural support for cells but also deliver bioactive substances to the targeted areas [169]. Since these scaffolds are typically created using advanced 3D printing techniques, they can possess the customized structure, permeability, and structural features required for specific applications [170]. These scaffolds are usually constructed from biocompatible materials such as hydrogels, ceramics, natural and synthetic polymers, and many more. One substance that can encourage cell adhesion and proliferation is hydrogel, which has a high-water content and resembles ECM. On the other hand, polymers with tunable breakdown rates, like poly (lactic-co-glycolic acid) (PLGA), allow for the controlled release of medications over time [171].

It is essential to use biodegradable and bioactive materials to improve scaffold designs. For scaffolds intended for short-term usage, biodegradable materials are crucial because they may be surgically removed after tissue regrowth [172]. A more natural transition is made possible by the growth of new tissue in place of the deteriorating scaffold. Bioactive substances, which can promote cellular functions like adhesion, proliferation, and differentiation, increase the regenerative efficacy of scaffolds. For example, the scaffold design can include specific growth factors or bioactive peptides to influence cellular response and facilitate tissue integration. The integration of chemical signals into the matrix, which in turn encourages specific cellular behaviors required for effective tissue regeneration, is essential to the scaffold’s functionality [173].

The scaffold’s biocompatibility and affinity for target cells can be enhanced by coating or functionalizing it with peptides and proteins, as it significantly affect the drug loading and release profile [174]. Consequently, this encourages the best possible cellular interactions. A good scaffold’s porosity, which allows cells to migrate and nutrients to disseminate, is another crucial characteristic for tissue regeneration. This is a difficult task: the scaffold must be both robust enough to withstand physiological stresses and permeable enough to permit cell infiltration and the movement of nutrients. Advances in 3D printing have made it possible for researchers to design scaffolds with precisely tailored properties, which makes them perfect for a variety of tissue engineering uses [175].

Drug-loaded scaffolds have shown new therapeutic applications in recent studies. One strategy for treating localized cancer has been to incorporate chemotherapy medications into 3D-printed scaffolds in order to minimize systemic toxicity and increase therapeutic efficacy at the tumor site. Furthermore, scaffolds designed for regenerative applications, including mending bone and cartilage, can include medications that promote the synthesis of growth factors, which support tissue regeneration and healing [176]. Because they facilitate continuous medication release and encourage functional tissue healing, these scaffold-based drug delivery methods hold promise for treating challenging medical conditions.

Curcumin and chloramphenicol have quite different solubility qualities in physiological situations because curcumin is hydrophobic while chloramphenicol is hydrophilic [177]. The 3D printing extrusion syringe inks containing curcumin and/or chloramphenicol loaded onto sodium alginate-cellulose nanofibers (SA-CNF) were developed. Their printability and shape fidelity were evaluated, by the drug-loaded inks underwent rheological characterization. Three-dimensional printing drug-loaded inks with shape fidelity and then freeze-drying or air-drying samples allowed for the achievement of a variety of morphological traits [178]. The development of functional medicinal forms was made possible by this technique [179]. Two different methods for controlling the distribution of medications over time were created based on the outcomes of the in vitro drug delivery tests: freeze-dried and Ca²⁺ crosslinked/air-dried. The former had a faster release performance in every scenario [180,181]. During drug delivery, strategies to control the release over a long period of time were used, considering the surface areas of the samples, the different CNF contents of the inks, and the different water solubility of the drugs (Figure 5).

Drug delivery scaffolds pose a challenging design problem that includes architectural considerations, surface modification, and material selection. Biocompatible, biodegradable, and bioactive components can significantly increase the effectiveness of 3D-printed scaffolds for tissue regeneration [182]. Scaffolds that deliver therapeutic chemicals in a controlled way can be developed by carefully adjusting these parameters, producing the intended biological response and promoting tissue regeneration and repair. Future research combining new materials, printing technologies, and customized DDS will increase our understanding of scaffold functionality and its applications in regenerative medicine [26].

4.1. Fundamental Design Considerations

When developing scaffold-based DDS for tissue regeneration, there are several crucial design considerations to make. Surface properties are one of the primary factors influencing scaffold design. A scaffold’s surface characteristics roughness, hydrophilicity, and chemical functionalization have a big influence on cell adhesion, proliferation, and differentiation. Rougher scaffolds, for example, have been shown to enhance biological responses by expanding the surface area accessible for cell adhesion and dispersion [183]. It is significant because it facilitates the scaffold’s improved integration with the surrounding tissue and accelerates the healing process when cells come into contact with materials. Adding bioactive substances, such as proteins or peptides, to scaffolds by altering their surface may improve their biological activity and have a direct effect on how well DDS works (Figure 6).

Because it significantly affects how fluids and nutrients pass through the material, pore size range is another crucial scaffold design feature [184,185]. A well-structured, permeable porous scaffold is required to facilitate cellular metabolism and proliferation. The optimal porosity range is between 60 and 80% to maximize tissue integration and cellular infiltration. The pore size is also crucial because studies show that pore diameters greater than 300 μm are best for promoting angiogenesis and nutrient flow. Scaffolds with the proper porosity and pore size enable the targeted distribution of drugs and facilitate the efficient influx of new tissue into the scaffold design, hence enhancing tissue regeneration outcomes [186]. When designing scaffolds, mechanical strength must also be considered. A scaffold’s mechanical properties need to mesh well with the surrounding tissue in order to support tissue effectively [187]. Scaffolds must be mechanically robust enough to withstand physiological forces in order to promote tissue healing; this is particularly crucial for specific applications such as bone or cartilage regeneration. The mechanical properties of 3D-printed scaffolds are highly dependent on variables such as the polymer’s molecular weight and the manufacturing process. By maximizing these variables, researchers can create scaffolds with the required load-bearing capability for load-bearing applications, including orthopedic implants. Therefore, finding a balance between mechanical properties and biological performance is essential for successful scaffold design [188].

In recent years, a lot of attention has been paid to methods that can enhance the loading and release patterns of medications within scaffolds [189]. One technique encapsulates pharmaceuticals in the scaffold material during printing, allowing for controlled drug release over time. Biodegradable polymers with specific degradation rates that correspond to the desired drug release patterns can be selected to further customize this method. For instance, in addition to offering sustained release of medicinal compounds, PCL can improve cell adhesion and proliferation. Hydrogels and polymers are examples of composites that can increase drug-loading capacity and provide multifunctional properties required for effective regeneration treatments. Another innovative strategy to maximize drug delivery is the use of stimuli-responsive polymers, which can release drugs in response to specific environmental triggers like pH, temperature, or biological signals [190]. These intelligent scaffolds can significantly improve medication delivery accuracy by regulating the release of treatments in response to particular circumstances, such as inflammation at the site of an injury. The use of anti-inflammatory scaffolds, which can recognize changes in the environment and selectively release medication, when necessary, is one example. During the healing process, this helps to enhance treatment efficacy and reduce negative effects. Additionally, advancements in 3D printing technology allow scaffold architecture to be modified. This makes it possible to create complex drug release systems that are tailored to the unique requirements of various tissues [191].

4.2. Biomimicry and Functional Modifications

Adding physiologically active substances to 3D-printed scaffolds is an essential strategy for enhancing their functionality and performance in tissue regeneration applications. Biomimicry, which aims to replicate natural materials and structures, has a significant positive impact on scaffold design [50,192]. Researchers can add bioactive materials, such as growth factors, peptides, or ECM components, to the scaffold matrix to enhance the circumstances for cell adhesion, proliferation, and differentiation. Scaffolds that release bio signaling molecules may promote angiogenesis, the process of guiding the formation of new blood vessels, to ensure that regenerated tissues receive an adequate quantity of nourishment. By improving tissue integration and facilitating the regeneration of organized tissue that works similarly to the original, this ability to mimic natural signaling settings helps to close the gap between state-of-the-art materials technology and biological healing processes [193].

Modifying scaffold materials chemically and physically is another way to increase scaffold compatibility with targeted therapies. One common objective of surface functionalization is to increase hydrophilicity or provide bioactive regions that encourage cellular interactions. Adding hydrophilic groups or bioactive chemicals to PCL scaffolds can enhance protein adsorption and improve cellular responses [194]. Techniques like co-electrospinning or mixing different polymers can be used to generate composite scaffolds with synergistic properties, which enhance overall performance in terms of drug loading and release kinetics. Functional changes, such as surfaces with certain nano topographies that mimic the environments seen in living cells, can be produced to enhance cellular behavior. Furthermore, complex geometries and structures that can contain physiologically active substances and control their release rates can be incorporated thanks to recent advancements in 3D printing [194]. With careful control, this technique could produce “smart” scaffolds that can sense changes in their surroundings, such as temperature or pH, and release therapeutic chemicals when they are needed. By delivering medications locally and reacting directly to the regeneration environment, these dynamic systems can help us improve therapeutic outcomes. Functionalized scaffolds that release anti-inflammatory medications in response to inflammatory markers are one potential solution to regulate local tissue reactions during the healing process [195]. Researchers have combined biomimetic notions with advanced material science and engineering to create highly customized scaffolds that support tissue regeneration and enhance it further through targeted therapeutic activities.

Prior research has demonstrated the effectiveness of bioactive components that enhance specific cellular behaviors within the scaffold microenvironment [196]. For example, the addition of growth factors or ECM proteins may activate certain signaling pathways to promote cell migration, proliferation, and differentiation of all crucial activities in tissue repair. Scaffolds with gradually biodegradable microenvironments can be designed to facilitate the controlled release of these bioactive components in order to replicate the temporal and spatial gradient observed in natural tissue healing dynamics [197,198]. By promoting tissue regeneration and promoting active involvement in the process through controlled drug release and physiological modulation, scaffolds with this type of strategic functionality can increase the effectiveness of therapeutic interventions. Creating 3D-printed scaffolds with physiologically active chemicals and functional modifications is crucial to improving tissue regeneration techniques. Understanding and applying biomimicry principles to scaffold design, together with a variety of physical and chemical modifications, can significantly improve scaffold performance and drug delivery efficacy. Future scaffolds can be developed to actively participate in tissue repair and regeneration instead of just acting as passive supports, which could lead to better patient outcomes in regenerative medicine applications [199].

5. Applications of 3D-Printed Scaffolds in Drug Delivery

5.1. Cancer Therapy

The use of 3D-printed scaffolds for targeted drug delivery in cancer treatment has generated a lot of interest since it may increase therapeutic efficacy while lowering systemic toxicity. Traditional ways of giving chemotherapeutic treatments sometimes result in considerable adverse effects since circulating drugs affect both malignant and healthy cells. Drug distribution to tumor sites using 3D-printed scaffolds may boost local medication concentrations while reducing systemic adverse effects. Doxorubicin-loaded PLGA scaffolds, for instance, have demonstrated the capacity to deliver chemotherapeutics locally and release them gradually; in preclinical models, these scaffolds successfully inhibited tumor growth [200,201,202].

The value of 3D-printed scaffolds in cancer treatment is illustrated by several recent case studies. Doxorubicin and PCL are two components of a composite scaffold developed by Ogay et al. (2020) targeted medication administration in the treatment of breast cancer. Chua et al. (2024) revealed that the great porosity of the 3D-printed PCL scaffold made it possible to adjust the drug loading and release profiles to meet the requirements of the local tissues [203,204]. An examination into scaffolds for the regulated release of proangiogenic and anti-inflammatory medicines suggests that 3D-printed scaffolds with microporous architectures could effectively support targeted treatment, improving healing outcomes in cancer excision procedures. These examples show how adaptable 3D-printed scaffolding techniques are for creating customized DDS for cancer therapy [26,205].

The likelihood of medication resistance can be minimized, encouraging optimal treatment outcomes. Modifying scaffold-based variables, such as drug loading, cellular penetration, and drug release kinetics, can enhance the robustness of 3D-printed scaffolds [206,207]. For example, scaffolds designed with gradient porous architectures improve drug retention and provide extended release, leading to localized pharmacokinetics. This scaffold-building process is particularly advantageous for advanced or metastatic cancers, as it can regulate the release of medicinal compounds to complement the body’s healing processes, where traditional treatments often fails [208].

Additionally, the integration of 3D-printed scaffolds with multi-modal therapy is now feasible due to advancements in materials science and printing technology. Synergistic outcomes can be achieved by combining chemotherapy with immunotherapy or targeted treatments, thanks to recent developments such nanoparticle encapsulation into scaffolds [209]. In a practical setting, scaffolds that release immune-modulating substances and anti-cancer medications may strengthen the host immune system and more successfully fend off remaining tumor cells. Combinatorial medication distribution via 3D-printed scaffolds may open the door to more personalized and focused cancer treatment strategies that take into consideration the distinct tumor profiles of each patient [29].

The use of 3D-printed scaffolds in cancer treatment has been a significant advancement in targeted drug delivery systems. By developing specialized scaffolding that can sustain the release of therapeutic molecules, researchers have begun to transform the oncology therapy landscape. Because these scaffolds can manage both mechanical requirements and biological interactions within tumor microenvironments, they offer a potentially novel approach to cancer treatment. Extensive research into 3D-printed scaffolds for drug delivery is anticipated to lead to advancements in personalized medicine, which will ultimately give cancer patients more effective and less invasive treatment options.

5.2. Bone and Cartilage Regeneration

The use of 3D-printed scaffolds for drug delivery in bone and cartilage regeneration has been a significant advancement in tissue engineering [210,211]. Bone and cartilage have different structures and functions; it may be challenging to regenerate them. Tissue-specific scaffolds should enable the targeted release of therapeutic medications that promote osteogenesis and chondrogenesis in addition to providing mechanical support. Biologically active substances are added to 3D-printed scaffolds to improve their capacity to affect cell behavior and intervention outcomes. Numerous studies have shown that scaffolds loaded with osteogenic substances, such as BMPs or VEFG, can help restore mechanical integrity and promote fracture healing. In an environment that closely mimics the natural ECM, scaffolds promote stem cell proliferation and differentiation towards bone or cartilage lineages while transporting essential therapeutic molecules [212].

Researchers have recently emphasized the need to include drug-releasing capabilities into scaffolds designed for bone regeneration. Three-dimensional-printed scaffolds made of PCL and HA showed promising results in facilitating drug release and fostering osteogenic differentiation. These scaffolds serve as both a physical scaffolding for tissue growth and an ideal drug delivery system. They allow therapeutic medications to be released over time, guaranteeing a consistent supply of the building blocks needed to produce new bones. The total efficacy can be increased by implementing particular therapeutic reactions throughout the healing process due to the design’s versatility. The scaffold designs have significantly expanded due to advancements in 3D printing and material composition. This progress allows for the production of scaffolds with hierarchical structures that meet the unique requirements of various tissue types and offer great therapeutic potential in regenerative medicine applications [35,213].

In addition to transporting medications and providing mechanical support, 3D-printed scaffolds must promote angiogenesis, a process essential to the effective regeneration of cartilage and bone (Figure 7). By adding vascularization techniques to these scaffolds, vital nutrients can be delivered to the regeneration tissues, improving outcomes. By boosting vascularization, studies have shown that the combination of scaffolds that release angiogenic factors and porous materials with spatial planning can greatly enhance the healing process. Dual-layer scaffolds have also been shown in studies to be an efficient way to regenerate osteochondral lesions. Scaffolds with interconnected channels can diffusely distribute growth factors and drugs that stimulate the formation of the underlying bone and aid in cartilage regeneration, bridging the gap between the two types of tissue.

The versatility of 3D printing technology makes it possible to create scaffolds with exact geometries and porosities that are tailored for various medical applications, increasing their effectiveness in delivering medications for bone and cartilage regeneration [214]. For example, creating scaffolds with different pore sizes can improve cell infiltration and nutrition exchange. Scaffolds with well-designed apertures have been found to improve osteoblastic differentiation and mineralization, two biological processes that are essential for bone healing. Additionally, the ability to print scaffolds with preset designs enhances their functionality, enabling a more regulated and effective healing response [215].

Lastly, the use of 3D-printed scaffolds for targeted drug administration in chondrocyte and bone regrowth is a revolutionary approach in regenerative medicine. By overcoming the traditional limitations of DDS and providing the necessary structural support for tissue healing, these scaffolds enhance the therapeutic potential of bioactive medicines [216].

5.3. Wound Healing and Soft Tissue Repair

The application of 3D-printed scaffolds to promote wound healing and soft tissue repair is one exciting new avenue in regenerative medicine. Soft tissue injuries, such as burns, ulcers, and surgical wounds, often require advanced therapeutic strategies to encourage effective healing while lowering the risk of side effects like infection and scarring. Three-dimensional-printed scaffolds can be utilized as temporary support structures to aid in tissue regeneration, at the site of the wound, these scaffolds promote cellular infiltration, nutrition diffusion, and regulated drug delivery [217]. These scaffolds can be tailored to mimic the distinct structure of the target tissue, which enhances the body’s natural healing capabilities and improves patient outcomes.

One significant benefit for wound healing is the ability to incorporate drug-releasing properties into 3D-printed scaffolds [218]. Three-dimensional-printed polysaccharide scaffolds activated by near-infrared light demonstrated encouraging results in enhancing diabetic wound healing. By incorporating these bioactive elements into the scaffold, tailored therapy is made possible, which releases therapeutic agents straight to the site of injury, accelerating the healing process and enhancing tissue integrity. Growth factors including VEFG and EGF, which are essential for fostering cell migration, proliferation, and angiogenesis, have also been studied in 3D-printed scaffolds [219].

The porous structure of 3D-printed scaffolds makes them ideal for wound healing. The interconnected pore structures that permit cell migration and infiltration, the microenvironment is perfect for tissue regeneration. The exchange of nutrients and oxygen is essential for effective wound healing, and porous scaffolds enhance this process. Scaffolds that are built with specific porosities and pore sizes might improve the retention of bioactive chemicals and encourage the development of new tissue. Promoting cellular activity is one of hydrogel scaffolds’ key roles; another is to keep wound moisture levels stable, which is essential for preventing wound desiccation and speeding up healing [220]. The versatility of 3D printing technology makes it possible to create customized scaffolds for soft tissue repair that are tailored to each patient’s unique needs. Custom scaffolds can be made to better integrate with the surrounding tissue and reduce the risk of complications by taking into consideration the particular characteristics and measurements of each patient’s wound. Further benefit of 3D printing is its ability to integrate several materials and functions into a single scaffold, expanding the potential applications for wound treatment. The creation of scaffolds that may release growth factors and antibacterial medications is one example; this enables the combination of numerous therapeutic methods [221].

Researchers are also looking into innovative scaffold designs, such creating materials that can mend themselves or react to stimuli, to further increase the efficacy of wound healing treatments. For instance, scaffolds can now use hydrophilic or stimuli-responsive materials to adjust to changes in the wound environment, such as pH or inflammatory markers. This makes it possible to promote localized healing responses or dynamically regulate drug release rates. Three-dimensional-printed scaffolds are evolving into increasingly sophisticated drug delivery platforms for wound healing applications, which will enhance patient outcomes and care [222].

Three-dimensional-printed scaffolds represent a significant advancement in tissue healing and wound treatment. By providing structural support and enabling targeted and controlled drug delivery, these scaffolds promote tissue regeneration and repair in a manner that traditional techniques cannot [223]. Regenerative medicine could undergo a revolution with the use of 3D-printed scaffolds for wound healing (Figure 8). With continued research and technological breakthroughs, more individualized and efficient treatment solutions for various soft tissue injuries may become conceivable [224].

6. Challenges and Limitations

Several technological obstacles that need to be addressed before 3D printing can be used as planned to create scaffolds for drug delivery in tissue regeneration [225]. Since it affects the scaffolding design’s faithfulness, the precision of 3D printing techniques is a serious concern. Variations in printing parameters, such as print speed, layer height, and nozzle diameter, may result in unsatisfactory final scaffolding. These differences can affect porosity, surface integrity, and mechanical properties, which can affect cell behavior and drug delivery effectiveness. To obtain the necessary level of precision, printing procedures and scaffold manufacturing tools must be continuously improved [226]. Porosity is another crucial scaffold design element that affects tissue regeneration and drug delivery. Scaffolds must have the proper porosity in order to promote cellular penetration, nourishment, and waste product exchange. However, excessive porosity may result in mechanical failure, particularly in weight-bearing applications such as bone repair. Optimizing the pore size and distribution is also required to attain the desired drug release patterns [227]. Finding a balance between the scaffold’s strength, permeability, and drug loading capacity is a significant challenge in 3D printing. Scaffold design is difficult; careful material selection and the application of advanced modeling techniques are required to attain the best structural and functional attributes [228].

Scalability of 3D printing technologies is important when considering the transition from small-scale models in the lab to larger-scale ones in the clinic. To achieve reproducibility, scaling up production using existing 3D printing techniques can be a bit of a problem. Ensuring that materials and structures stay consistent throughout large batches is a significant concern. This disparity complicates regulatory approval and acceptability in clinical settings because all manufactured scaffolds must adhere to strict quality standards. Therefore, it is crucial to develop standardized protocols and enhance printing technologies in order to progress scaffold-based DDS in regenerative medicine [229]. Knowing and adhering to relevant rules is a significant barrier to implementing scaffold-based DDS from the lab to the clinic. However, the current regulations do not sufficiently address the unique characteristics of 3D-printed scaffolds. For instance, the variety in material qualities and manufacturing processes makes it difficult to generate consistent safety profiles. Thus, rigorous testing procedures are required to assess mechanical performance, biocompatibility, and degrading behavior. As the field develops, clear regulatory frameworks tailored to 3D bio-printed materials are increasingly required to facilitate clinical translation and ensure patient safety [230].

Evaluating the safety of innovative biomaterials used in 3D-printed scaffolds is urgently needed, in addition to the challenges of complying with regulatory standards. As the breakdown of products of biodegradable materials may result in systemic toxicity or inflammatory reactions, comprehensive toxicological studies are essential. It is vitally important to understand how materials interact with biological systems when scaffolds are combined with bioactive substances or medicinal drugs. Longitudinal studies are frequently required to assess the long-term impacts of scaffolds in biological environments because some unfavorable reactions could not show up until after prolonged exposure. Finding safe and efficient biocompatible materials must be the main goal of research if scaffold-based DDS are to be trusted in clinical settings [231]. Establishing a consistent manufacturing process for 3D-printed scaffolds that guarantees quality and repeatability across batches is essential to further lowering the risks associated with regulatory compliance. Thorough documentation of the production process and scaffold characterization are necessary to guarantee adherence to regulatory standards [232]. By being involved early on, regulatory organizations can provide crucial assistance and facilitate progress. Scaffold-based medication delivery systems will be safer and more dependable when regulatory considerations are combined with ongoing advancements in materials science and 3D printing technology. As a result, there will be more confidence in their implementation in different therapeutic settings [233].

7. Future Directions

The integration of smart technology into 3D-printed scaffolds is an intriguing new step towards bettering drug delivery systems, especially for tissue regeneration treatments. Intelligent scaffolds are designed to respond dynamically to environmental stimuli such as pH, temperature, light, or ultrasound in order to provide controlled and targeted drug release that is in harmony with biological processes. Alternatively, stimuli-responsive polymers can be used, such as poly (N-isopropylacrylamide) (PNIPAm), which at certain temperatures can transition from a hydrophilic to a hydrophobic state [234]. These features can be utilized to create DDS that release therapeutic molecules just in the designated area, minimizing undesirable side effects and increasing treatment effectiveness. As tumors and inflammatory tissues frequently have acidic microenvironments, materials that are sensitive to pH can release drugs in reaction to these environments, hence improving the specificity of therapy [235].

The incorporation of nanotechnology into 3D-printed scaffolds offers exciting new opportunities to increase drug delivery effectiveness. By adding nanoparticles to scaffold designs, which improve drug solubility, stability, and bioavailability, a more powerful therapeutic response can be achieved [236]. The use of ultrasonic-responsive nanocarriers, which release medications precisely in response to ultrasound stimulation, is one non-invasive method of delivering targeted medications to sick tissues. Moreover, nanocarriers designed to engage in passive or active targeting based on their intrinsic characteristics or surface modifications can be used to deliver drugs directly to particular cell or tissue types. Combining these nanotechnology applications with 3D printing techniques can result in a highly functioning scaffold that can address complex medical issues [237].

The viscoelastic properties of scaffolds enable them to respond similarly to natural tissues, which is significant in areas that are subjected to repeated loads or weight [238]. The significance of viscoelasticity in cartilage tissue engineering is highlighted by Duan et al. (2021) in their study, with particular reference to the stress relaxation characteristics of scaffolds [239]. This finding implies that by better accommodating the physiological motions of the cells they encapsulate, scaffolds with the proper viscoelastic properties can enhance the health and functionality of the cells [239]. According to Liang et al. (2022), 3D-printed scaffolds respond differently to mechanical loading due to their structural design [240]. Their study demonstrated that the scaffold undergoes two distinct phases of creep and stress relaxation in response to stress, exposing a transitory response that may affect the behavior of cells inside the structure [240]. Understanding these mechanical characteristics must be the primary objective for future designs, particularly when working with dynamic biological environments.

The interactions between natural and synthetic polymers have a significant impact on the viscoelastic properties of composite scaffolds [29]. Leung and Naguib (2012) described composite scaffolds with improved mechanical performance; nevertheless, caution was suggested since increasing filler content could affect mechanical properties due to poor interface integrity [241]. In addition to bearing mechanical pressures, scaffolds composed of carefully designed composites can enhance cell adherence and proliferation in response to biological cues [241]. Liu et al. (2022) demonstrated that scaffolds with a liquid crystalline phase have the ability to create a microenvironment that resembles the characteristics of ECM found in nature, hence enhancing cellular behavior [242]. Viscoelasticity is crucial for creating scaffolds that encourage the best possible cellular interactions and help guide the stem cell differentiation processes necessary for tissue regeneration [243].

Future studies must focus on developing new material formulations and structural designs to increase the viscoelastic properties of scaffolds. Prosecká et al. (2015) looked into how adding PCL nanofibers could improve the viscoelastic characteristics of collagen/HA scaffolds for the purpose of bone regeneration [244]. With these adjustments, the mechanical performance of scaffolds and functionality can be further enhanced, making them appropriate for a wide range of regenerative medicine applications [85].

Regenerative technologies have a lot of potential for personalized medicine, which might result in the creation of scaffolds and drug formulations tailored to individual patients that could be utilized to tailor treatment regimens to meet particular needs. Recent advancements in 3D printing, customized scaffolds that precisely match the size, form, and function of a patient’s injured tissue may now be designed and manufactured [245]. Scaffolds that precisely match the necessary dimensions can be created and fabricated to better aid tissue regeneration by employing imaging data to create patient-specific 3D models. By customizing the approach for every patient, the integration and healing processes can be maximized and raise the possibility of favorable patient outcomes in terms of scaffold functionality and compatibility [246].

Within these custom scaffolds, individualized DDS can be incorporated to further optimize treatment approaches based on specific patient characteristics. By examining the genetic, metabolic, and environmental sickness profiles of each patient, it is possible to customize the release of drugs or growth factors on scaffolds to meet their specific needs [247,248]. Scaffolds pre-loaded with specific growth factor combinations can significantly improve treatment outcomes by accelerating the healing process for patients whose recovery is slower due to comorbidities. This innovative approach to regenerative medicine, which blends scaffolding technology with patient-specific medication compositions, has made it possible for healthcare professionals to offer more individualized, effective treatments that are in line with distinct patient profiles and needs [249]. The prospect of fusing smart technology with customized medical practices is encouraging for scaffold-based DDS going forward [250]. In order to better respond to biological signals and be customized to meet the specific needs of each patient, researchers must continue to refine scaffold designs. If these cutting-edge techniques are effectively applied to tissue regeneration, patients in need of complex biological therapies may receive better care [232].

8. Conclusions

In the end, 3D-printed scaffolds are revolutionary in the field of drug delivery for tissue regeneration because of their ability to create tailored constructs that optimize mechanical strength and biological activity. By incorporating cutting-edge materials and drug delivery techniques into these scaffolds, researchers can enhance the localized therapeutic efficacy and encourage efficient tissue healing and regeneration. In order to properly utilize 3D-printed scaffolds in therapeutic contexts, further multidisciplinary research is needed. We can improve these novel scaffolds for more potent regenerative medicine solutions while tackling persistent issues with accuracy, scalability, and regulatory compliance by bringing together materials scientists, biologists, pharmacologists, and clinicians.