Advancement of 3D Bioprinting Towards 4D Bioprinting for Sustained Drug Delivery and Tissue Engineering from Biopolymers

Abstract

The transition from three-dimensional (3D) to four-dimensional (4D)-bioprinting marks a significant advancement in tissue engineering and drug delivery. 4D-bioprinting offers the potential to more accurately mimic the adaptive qualities of living tissues due to its dynamic flexibility. Structures created with 4D-bioprinting can change shape in response to internal and external stimuli. This article reviews the background, key concepts, techniques, and applications of 4D-bioprinting, focusing on its role in tissue scaffolding and drug delivery. We discuss the limitations of traditional 3D-bioprinting in providing customized and sustained medication release. Shape memory polymers and hydrogels are examples of new responsive materials enabled by 4D-bioprinting that can enhance drug administration. Additionally, we provide a thorough analysis of various biopolymers used in drug delivery systems, including cellulose, collagen, alginate, and chitosan. The use of biopolymers in 4D-printing significantly increases material responsiveness, allowing them to react to stimuli such as temperature, light, and humidity. This capability enables complex designs with programmable shape and function changes. The expansion and contraction of hydrogels in response to temperature changes offer a practical method for controlled drug release. 4D-bioprinting has the potential to address significant challenges in tissue regeneration and medication administration, spurring ongoing research in this technology. By providing precise control over cell positioning and biomaterial integration, traditional 3D-bioprinting has evolved into 4D-bioprinting, enhancing the development of tissue constructs. 4D-bioprinting represents a paradigm shift in tissue engineering and biomaterials, offering enhanced possibilities for creating responsive, adaptive structures that address clinical needs. Researchers can leverage the unique properties of biopolymers within the 4D-printing framework to develop innovative approaches for tissue regeneration and drug delivery, leading to advanced treatments in regenerative medicine. One potential future application is in vivo tissue regeneration using bioprinted structures that can enhance the body’s natural healing capabilities.

1. Introduction

Three-dimensional (3D) bioprinting is a state-of-the-art technique that creates complex biological constructs filled with living cells by fusing bioengineering and additive manufacturing [1,2]. This technique produces intricate tissue models that are physically and functionally equivalent to actual biological tissues using bioinks, which are printable materials that incorporate living cells [3,4]. Although the foundation for 3D-bioprinting was laid in the 1980s by conventional 3D-printing techniques, the area has advanced significantly in the past 20 years, particularly in tissue engineering and regenerative medicine [5]. From its early days of focusing on the mechanical properties and design of 3D-printed structures, bioprinting has advanced significantly [6,7]. However, the addition of living cells to these frameworks has significantly expanded the capabilities and applications of bioprinting, resulting in the development of scaffolds that can promote tissue growth and regeneration [8].

Compared to the more straightforward layering methods employed in the early days of 3D-bioprinting, extrusion-based procedures, inkjet printing, and laser-assisted bioprinting have significantly increased the complexity and accuracy of bioprinted objects [9,10]. For instance, structures smaller than 50 μm can be made using high-definition (HD) bioprinting, which results in more accurate and high-resolution printed tissues [11,12]. Owing to efforts by researchers to improve the technology and materials used in the process, bioprinting is rapidly moving towards complex, multi-material systems that can support improved cell behavior and tissue function [13,14]. This covers the creation of composite hydrogels and responsive materials. This trajectory opens the door to 4D-bioprinting and may brighten the future of drug testing and disease research. This method makes it possible for bioprinted objects to include stimuli-responsive features, which may result in long-term medication delivery and dynamic tissue engineering applications.

4D-bioprinting is a fascinating development in the field of biofabrication that incorporates time as a dynamic component into conventional 3D-bioprinting procedures [15,16]. With the use of this advanced technology, scaffolds that can adapt to changes in temperature, pH, or biological signals can be created that alter their structure and function in accordance with preset programming [17,18]. Artificial structures that behave more like real tissues can be created by reproducing complex tissue dynamics and developmental processes by incorporating the fourth dimension. By creating scaffolds with exceptional properties that improve functionality like self-assembly, flexibility, and evolution, 4D-bioprinting has the potential to revolutionize tissue engineering [15,19]. These characteristics are crucial for domains such as drug delivery systems and regenerative medicine.

Using 4D-bioprinting to create new smart biomaterials (SBMs) could greatly increase the effectiveness of medicine delivery systems. SBMs demonstrate responsive behavior by changing their properties based on variations in environmental parameters such as light, heat, pH, and moisture [20]. When used in 4D-bioprinting, these materials enable structures to continuously adapt, altering their shape or function in response to specific stimuli. With these materials, it is possible to release therapeutic chemicals at the target site under regulated conditions in response to certain physiological signals. By enabling the creation of better drug delivery systems with sustained release profiles, 4D-bioprinting improves treatment outcomes and reduces negative effects related to conventional drug administration techniques [21]. It is possible to use responsive materials that can alter shape in response to the body’s natural healing processes to generate bioprinted tissue scaffolds, medication carriers, and customized medical devices. 4D-bioprinting has the potential to transform healthcare by resolving long-standing issues with drug delivery and tissue regeneration, two fields in which research is continuously advancing [22].

Focusing on biopolymer-based continuous drug administration, this review aims to compare advancements in 4D-bioprinting with those in 3D-bioprinting. Traditional 3D-bioprinting techniques have revolutionized tissue construct creation by allowing precise control over cell placement and biomaterial incorporation. 4D-bioprinting has evolved to adapt its shape in response to temperature, light, and humidity [23]. This capability, combined with the extended release of therapeutic molecules, holds promise for developing sophisticated drug delivery systems that can adjust to physiological conditions, enhance efficacy, and improve patient compliance. By analyzing key advancements in materials science and bioengineering facilitating the shift to 4D-printing, this study aims to identify potential uses and strategies for integrating bioprinting technologies in pharmaceutical research and regenerative medicine. This study will explore gaps in our current understanding, especially regarding how 3D-bioprinting technologies interact with biopolymers, which can influence drug delivery efficacy [24]. This approach seeks to inspire further research addressing the limitations of existing drug delivery techniques and to generate innovative ideas for developing responsive and efficient biomimetic systems.

2. Fundamentals of 3D-Bioprinting

3D-bioprinting is a significant advancement in tissue engineering and regenerative medicine because it enables the layer-by-layer creation of intricate tissue architectures [25,26]. 3D-bioprinting depends on the deposition of biological elements, such as living cells and suitable scaffolds, to create artificial tissues, as shown in Figure 1, that closely resemble their natural counterparts [27]. This method uses bioinks, which are materials composed of cells, biopolymers, and other additives, to create three-dimensional structures that promote tissue function and cell survival [28,29]. By altering the spatial distribution and arrangement of cells and biomaterials to resemble the intricate architecture of natural tissues, researchers can increase the likelihood of successful integration and functionality in vivo [30].

Numerous techniques have emerged in the field of 3D-bioprinting, each with unique advantages and possible applications [31]. Among the most popular methods are extrusion-based printing, inkjet printing, and bioprinting with laser help [32,33]. In extrusion-based printing, which usually uses a pneumatic or mechanical system, the continuous deposition of bioinks allows the creation of intricate geometries and massive scaffold structures [34,35]. Thermal or piezoelectric actuators are used to release tiny droplets of bioink, giving inkjet printing its accuracy and resolution. However, laser-assisted bioprinting is perfect for creating vascular networks and other high-resolution tissue structures because it uses laser light to precisely deposit bioink droplets onto substrates [36,37].

There are numerous potential applications for 3D-bioprinting in fields as varied as drug delivery, tissue engineering, and regenerative medicine [19]. 3D-bioprinting is used in regenerative medicine to produce scaffolding for a variety of tissues, such as bone, cartilage, and skin [38]. In order to aid in tissue regeneration, scientists can construct scaffolds out of biocompatible materials that cells can adhere to and develop on before being broken down by enzymes [39,40]. By using 3D-bioprinting to produce micrometric structures that may release medicinal compounds over time in a regulated manner, treatment efficacy can be further increased while negative effects are minimized [41]. Additionally, printing tissues with features resembling vasculature demonstrates the extent to which we can develop complex organs capable of supporting metabolic processes.

Figure 1 illustrates the evolution of printing technology over time, beginning with conventional methods and progressing to advanced 4D-bioprinting. At each technological stage, a key objective is to enhance the responsiveness, functionality, and design of drug delivery systems [42]. Conventional techniques, such as static 3D scaffolds and electrospun mats (2D), provide foundational support for drug release but are limited by passive delivery and a lack of dynamic interaction with the biological environment (Figure 1A). In contrast, 3D-printing technology enables the construction of porous objects with controlled release kinetics and more complex geometries. The development of printable filaments and customized 3D architectures enhances therapeutic precision and improves drug encapsulation and spatial distribution efficacy (Figure 1B).

Advancements in 3D-bioprinting involve the use of living cells and other biological components, enabling the creation of biomimetic drug delivery systems that can locally and continuously release medications while integrating with the host (Figure 1C). The latest innovation is 4D-bioprinting, which incorporates time as a fourth dimension. These structures can be programmed to change their shape, structure, or function in response to environmental stimuli such as pH, temperature, or enzymes [43]. This adaptability makes smart drug delivery systems possible, allowing them to respond to physiological cues by releasing therapeutic molecules in a controlled manner, thereby enhancing treatment effectiveness and reducing side effects (Figure 1D). Thus, the progression from 2D to 4D-printing reflects technological advancement and represents a significant step toward developing personalized, stimuli-responsive drug delivery systems.

Even though 3D-bioprinting has advanced significantly, a number of challenges remain that require ongoing study and development [44,45]. Finding bioinks that maintain cell viability and mechanical stability while degrading at the appropriate rates is a significant challenge [46]. Therefore, there is an urgent need for standardized methods for assessing the biological performance and clinical suitability of printed structures. Addressing these issues and creating bioprinting methods are essential to the successful transition from bench to bedside.

Limitations of 3D-Bioprinting

Even though recent developments in bioprinting technology have provided promising solutions to tissue engineering challenges, several issues remain before we can effectively create functional tissues. One major limitation is the control of microarchitecture [47]. The bioprinter’s ability to precisely manage the distribution and shape of cells is crucial for the functionality and integration of the printed tissue with the host tissue. Poorly organized tissues can hinder implant integration and function, leading to implant failure or decreased efficacy after implantation [48]. Improved calibration and new printing methods have been proposed to address this limitation. Many of these techniques involve adjusting parameters of the printing process, such as nozzle shape, printing pressure, and speed, to enhance tissue realism during manufacturing [49].

Selecting appropriate bioinks is another significant challenge, as many existing materials lack the mechanical strength and biocompatibility necessary for various functional tissues. Low-quality bioinks can severely limit the types of tissues that can be successfully printed, increasing the risk of implant failure [50]. There is an ongoing effort to develop new bioinks with enhanced mechanical and biocompatibility properties to overcome this hurdle. One promising avenue is the development of hydrogels that respond to temperature variations or utilize peptide self-assembly; these materials can provide the necessary structural support while creating optimal conditions for biological activity. This advancement could lead to the creation of more complex and functional tissue constructs for use in various biological applications [51]. Another significant challenge is maintaining scalability from lab-scale production to clinically viable output [52]. Scalability issues with bioprinting technologies may hinder patient access to innovative tissue engineering solutions. Standardization and automation of every production stage are essential to tackle this problem. Utilizing modular printing technologies, multi-nozzle printing, or parallel printing could enhance scalability and repeatability [53]. These approaches could improve tissue manufacturing efficiency and ensure consistency, potentially leading to increased use of bioprinted tissues in clinical settings.

Furthermore, significant ethical issues associated with bioprinting technologies must be addressed. Concerns regarding the sourcing of materials, bioprinted tissues, and consent raise important challenges related to legal frameworks and public trust. Developing multidisciplinary ethical standards and oversight mechanisms that incorporate the perspectives of all relevant stakeholders is necessary to comprehensively address these ethical dilemmas [54]. Lastly, integrating bioprinted tissues with living organisms presents additional challenges. Inadequate vascularization in printed tissues severely limits nutrient and waste flow, resulting in decreased tissue survival and compromised functionality. Strategies such as incorporating vascular cues (like vascular endothelial growth factor, or VEGF), employing coaxial bioprinting methods, or using sacrificial bioinks may enhance vascular integration [55]. The advent of 4D-bioprinting, which allows printed structures to dynamically change in response to environmental stimuli, has opened new possibilities for improving tissue integration and functionality in vivo. By addressing these challenges, researchers can advance bioprinting and pave the way for the successful therapeutic application of engineered tissues. It is essential to carefully address and improve these factors to ensure that bioprinted tissues perform as intended and remain effective over the long term (

Table 1. Limitations in 3D bioprinting for tissue engineering and regenerative medicine.

Limitation	Description	Consequences	Potential Solutions	Refs.
Microarchitecture Control	Difficult to achieve precise control over tissue structure and cell distribution during bioprinting.	Impaired tissue functionality and poor integration with host tissue.	Improved calibration and advanced printing techniques, with improved parameters (e.g., nozzle geometry, pressure, speed).	[56,57]
Bioink Selection	Existing bioinks often lack ideal mechanical strength and biocompatibility.	Limits the range of functional tissues; raises the risk of implant failure.	New bio-inks with improved mechanical properties and biocompatibility, e.g., peptide self-assembled or temperature-responsive hydrogels.	[58,59]
Scalability	Hard to scale up from lab-scale to clinically or commercially viable production.	Limited commercial applications and reduced patient access.	Standardize and automate processes; adopt modular, multi-nozzle, or parallel printing platforms.	[60,61]
Ethical Considerations	Questions around consent, material sourcing, and the implications of bioprinted tissues.	Potential legal hurdles and erosion of public trust.	Establish multidisciplinary ethical guidelines and oversight frameworks.	[62,63]
Integration with Living Organisms	Lack of vascularization restricts nutrient/waste transport in printed tissues.	Reduced tissue survival and compromised function.	Incorporate vascular cues (e.g., VEGF), sacrificial bioinks, coaxial techniques, and 4D-bioprinting approaches.	[64,65]

).

3. Advancements Towards 4D Bioprinting

A significant advancement in biofabrication technology, the transition from 3D to 4D-bioprinting signifies the incorporation of time as an inherent element that improves the operation of bioprinted structures [66,67]. This advancement is primarily driven by the use of stimulus-responsive materials, which may change in reaction to outside stimuli. This makes it possible to create assertive biological constructs that can mimic the physiological state of actual tissues [57,68]. 4D-bioprinting extends 3D-bioprinting by adding a temporal dimension that allows printed bio samples to change their conformation in response to environmental stimuli, including pH, temperature, and light [69,70].

Recent research has shown that 4D-bioprinting has promising new applications in regenerative medicine and tissue engineering [71]. Additionally, with the development and use of multi-material bioprinting techniques, scientists can advance the science of tissue engineering by creating intricate structures with diverse characteristics [72]. This makes it possible to adjust the scaffolds’ biological and physical properties, which is a significant advancement. The emergence of 4D-bioprinting has created new avenues for the creation and application of SBMs with desirable properties, like shape memory and self-healing, which is encouraging for their potential application in medical contexts [73].

The enhanced ability of biomaterials to dynamically react to external stimuli significantly increases the potential of 4D-bioprinting [74]. These materials need to undergo structural and functional changes for applications such as tissue regeneration, which is crucial for improving cellular connections and enhancing biocompatibility. By leveraging the capabilities of 4D-bioprinting technology, we can create living, flexible tissues that effectively respond to their physiological environment, leading to a paradigm shift in biofabrication [75]. Additional advantages of 4D-bioprinted dynamic structures that improve the regeneration of complex tissues like cardiac muscle and cartilage include improved cellular connections and increased biocompatibility [76]. By transforming 3D-printing from static models to living, breathing entities that can respond to their environment, 4D-bioprinting represents a paradigm shift in biofabrication [77]. It is anticipated that this innovation would significantly increase the efficacy of tissue engineering techniques by opening the door for the development of materials and structures that more accurately mimic the complexities of human tissues. 4D-bioprinting is setting the standard for next-generation medical solutions by fusing contemporary materials science with biofabrication concepts [78]. Its objective is to bridge the gap between clinical application and laboratory research. Figure 2 illustrates the benefits and limitations of both 3D and 4D-bioprinting and their impact on biomedical engineering. Traditional 3D-bioprinting allows for the layer-by-layer construction of static structures used to create complex prototypes, customized implants, and medical equipment. Its main advantages include design freedom, rapid prototyping, and reduced production waste [79]. However, limitations include restricted construction volumes, surface smoothness and resolution issues, and material availability.

Building on 3D methods, 4D-bioprinting employs intelligent materials that respond to environmental cues (such as pH, temperature, or enzymes) and incorporates time-dependent transformation [80]. This versatility enables novel applications such as self-assembling tissues, bio-robotic components, and responsive drug delivery systems. Advantages include enhanced functionality, self-healing capabilities, and dynamic performance. However, these benefits come with drawbacks, including complexity, increased production costs, limited choices of responsive materials, and the need for precise control over stimulation conditions [81]. This comparison reveals a significant shift in the development of next-generation drug delivery platforms: moving from passive, structurally stable structures (3D) to intelligent, functional systems (4D) that can interact with and adapt to biological environments.

4. Biopolymers for 4D-Bioprinting

A significant advancement in biofabrication, 4D-bioprinting with biopolymers opens up fascinating new possibilities for tissue engineering and intelligent drug delivery [82]. Now, researchers can create structures using stimuli-responsive materials that, like genuine tissues, can alter shape and function over time in response to environmental elements like light, pH, and temperature [83]. This section addresses the role and potential applications of various biopolymers to enhance the capabilities of 4D-bioprinting, as shown in Table 2. A detailed step of the 4D-bioprinting procedure is shown in Figure 3, illustrating how design, materials, and stimuli combine to produce living tissue. The core of the process is the 4D-bioprinting platform, which includes multiple input components. Smart bioinks are formulations containing cells and stimuli-responsive materials, while the biological components consist of living cells [84]. SBMs, which can change their structure or function in response to external stimuli, are another key element. The process begins with concept design, which involves envisioning the final form and purpose of the construct [85]. This is followed by the specification of the printer’s layer-by-layer material deposition procedure, known as the 4D-printing path. Smart design and simulation techniques digitally model the expected behavior under various conditions to enhance the printed product before manufacturing [86].

The printed structure is then exposed to appropriate external stimuli that induce transformation. These stimuli can include changes in ambient conditions such as light, magnetic fields, humidity, or pH. The printed structure may undergo a form change, like folding or bending, or an operational change, such as material release or bioactivity activation [80]. Natural chemicals called biopolymers are potential materials for tissue engineering because of their biodegradability and biocompatibility [87]. Because of their unique properties, bioinks that are appropriate for 4D-bioprinting can be developed, which leads to the development of dynamic scaffolds that can respond to their environment.

Alginates, biopolymers made from brown algae, are widely used in bioprinting due to their high gelation capabilities and biocompatibility. Alginate and shape-memory hydrogels can be combined in 4D-printing to produce printed structures that can adapt to variations in ionic strength and temperature by taking on predetermined shapes [88]. Gelatin is another biopolymer that has been widely used in tissue engineering. Because of its inherent biocompatibility and reversible thermal gelation properties, 4D-bioprinted scaffolds manufactured from it are a likely bet [89,90]. Gelatin-based hydrogels have the ability to change shape in response to environmental stimuli, such as temperature, mimicking the behavior of injured or damaged tissues throughout the processes of healing and regeneration.

Derived from chitin, chitosan is a biopolymer with exceptional antibacterial and biocompatible properties [91]. Functionalization of 4D-bioprinted chitosan scaffolds to enhance drug delivery systems can result in both structural modifications of the hydrogel and the controlled release of medicinal medicines. Using biopolymers in 4D-bioprinting is guided by the principles of shape memory and environmental reactivity [74]. The transition is made feasible by the distinct chemical and physical properties of the biopolymers used. According to recent research, modifying chemicals like polydopamine can be added to biopolymers to increase their responsiveness [92]. This gives printed constructions greater control over the amount and rate of dimensional change. For example, they demonstrated a 4D-biofabrication approach that uses graded hydrogel scaffolds that can respond to environmental stimuli and claimed significant advancements in the development of scaffolds that change shape over time, boosting their functional performance [93].

Red algae produce the polymer carrageenan, which is biodegradable and well-known for its bioactive properties [94]. This polymer has garnered significant attention in biomedical applications, particularly in skin bioengineering and wound healing, due to its ability to create an optimal environment for cell proliferation and tissue formation. Additionally, carrageenan shows promise in dynamic bioprinting environments, where it can be used to develop long-term drug delivery systems due to its responsiveness to temperature and humidity changes [95]. Research into the incorporation of carrageenan with other biopolymers may lead to the creation of sophisticated bioinks that can respond to physiological changes, potentially enhancing therapeutic outcomes in tissue engineering and regenerative medicine.

Table 2. Polymers in 4D-bioprinting.

Polymer	Description	Applications	Stimuli Response Mechanism	Refs.
Alginates	Biocompatible, biodegradable gel-forming polymers from brown algae.	Hydrogel scaffolds with shape memory for tissue engineering.	Responsive to temperature and ionic strength (Ca2+ cross-linking).	[96,97]
Gelatin	Biocompatible polymer that undergoes thermal gelation.	Dynamic scaffolds mimicking natural tissue healing.	Responds to temperature variations (sol–gel transition).	[98]
Chitosan	Antimicrobial polymer derived from chitin.	Scaffolds for controlled drug delivery.	Responds to pH changes (protonation of amino groups).	[99,100]
Polydopamine	Enhances polymer responsiveness for dynamic control.	Improves control in hydrogel formulations.	Increases sensitivity to various external stimuli (light, pH, heat, humidity, fields).	[101,102]
Carrageenan	Biodegradable polymer with bioactive properties from red algae.	Used in wound healing and skin bioengineering.	Responds to environmental stimuli (moisture, temperature).	[103,104]

Table 2. Polymers in 4D-bioprinting.

Polymer	Description	Applications	Stimuli Response Mechanism	Refs.
Alginates	Biocompatible, biodegradable gel-forming polymers from brown algae.	Hydrogel scaffolds with shape memory for tissue engineering.	Responsive to temperature and ionic strength (Ca2+ cross-linking).	[96,97]
Gelatin	Biocompatible polymer that undergoes thermal gelation.	Dynamic scaffolds mimicking natural tissue healing.	Responds to temperature variations (sol–gel transition).	[98]
Chitosan	Antimicrobial polymer derived from chitin.	Scaffolds for controlled drug delivery.	Responds to pH changes (protonation of amino groups).	[99,100]
Polydopamine	Enhances polymer responsiveness for dynamic control.	Improves control in hydrogel formulations.	Increases sensitivity to various external stimuli (light, pH, heat, humidity, fields).	[101,102]
Carrageenan	Biodegradable polymer with bioactive properties from red algae.	Used in wound healing and skin bioengineering.	Responds to environmental stimuli (moisture, temperature).	[103,104]

The development of 4D-bioprinting using biopolymers has opened up new opportunities for developing medication delivery systems with dynamically customizable release patterns based on physiological factors. The successful improvement in cartilage synthesis utilizing 4D-bioprinted self-folding scaffolds may serve as evidence of the capacity of biopolymer-based scaffolds to not only provide structural integrity but also actively engage in tissue regeneration processes [105,106]. The use of biopolymers in the 4D-bioprinting framework is a significant advancement in bioprinting technology that could revolutionize tissue production and medication delivery [107]. By using the dynamic properties of biopolymers to create bioactive structures that adapt to their surroundings, researchers can create innovative solutions that facilitate efficient healing and regeneration. The more biopolymer characteristics and processing technologies are studied, the more therapeutically relevant applications in regenerative medicine will be made possible [108,109].

Understanding the mechanisms of biopolymers is crucial for realizing the full potential of 4D-bioprinting technology. These mechanisms enable biopolymers to dynamically respond to their environments, enhancing their functionality and applicability in biomedical settings [110]. The ability of biopolymers to change shape and properties in response to environmental stimuli—such as light, temperature, pH, and chemical signals—is essential for improving drug delivery systems and regenerative scaffolds [111]. This responsiveness is particularly important in situations requiring individualized treatment approaches, as it allows for precise management of medication release profiles that can adapt to physiological factors. Researchers can leverage these pathways to develop bioactive materials that actively support tissue regeneration processes and effectively transport medications, thereby promoting effective healing and regeneration [112]. By examining the various properties and processing methods of biopolymers, we can gain a clearer understanding of how to produce them for specific therapeutic outcomes [113]. In the next section, we will delve deeper into the mechanisms of responsive materials in 4D-printing, exploring how these fundamental characteristics enable complex applications, facilitate tissue integration, and support innovations such as self-assembling constructs and responsive scaffolds tailored to patient-specific needs.

4.1. Mechanisms of Responsive Materials in 4D-Printing

4D-printing extends the capabilities of traditional 3D-printing by enabling the creation of structures that may dynamically change their shape in response to external influences [114,115]. The “fourth dimension” is all about the gradual shift that is enabled by responsive materials as shown in Table 3. These materials are often associated with traditional 3D-bioprinting techniques; their unique characteristics also make them suitable for advancements in 4D-printing, particularly regarding time-dependent responses to external stimuli [116]. These transitions are made possible by a number of crucial mechanisms, including stimuli-responsive hydrogels, hygroscopic reactions, and shape memory effects [117].

4.1.1. Shape Memory Polymers (SMPs)

Shape memory polymers (SMPs) are a class of smart material that may return to a predefined shape when exposed to external stimuli such as heat or electromagnetic waves [118,119]. These polymers, such as polyurethane, are highly advantageous for biomedical device applications and soft robotics because they can dynamically change shape to meet various functional requirements [120]. The integration of SMPs into multiple 4D-bioprinting applications demonstrates their ability to create structures that actively respond to environmental changes, thereby influencing treatment outcomes. This capability is attributed to their rapid response time, which typically ranges from seconds to minutes [121].

The capacity to program the material to temporarily shape itself during manufacturing is a crucial feature of SMPs [122]. After passing through a phase transition in response to an external stimulus, the material might revert to its original shape. A basic SMP consists of two parts: the soft section and the hard permanent part. The permanent phase provides structural stability, while the soft phase allows for reversible deformation. Because of their sensitive nature, which enables them to withstand significant bending and stretching, SMPs are ideal for applications requiring dynamic shape changes, such as bioengineering [123,124]. Recent developments in 4D-printing technology have made it possible to manufacture complex structures that can self-reshape in response to temperature stimuli. By creating actuators that mimic biological movements, studies have demonstrated that thermoresponsive SMPs can enhance the performance of soft robotics and biomedical equipment [125].

4.1.2. Hydrogels

Hydrogels are networks of water-absorbent polymers that have the ability to swell and contract, making them intriguing materials for 4D-printing [9]. The sensitivity of hydrogels depends on a number of variables, including temperature, pH, humidity, and ionic strength [126]. Size enlargement and reduction is a feature that, depending on the environmental conditions, drives hydrogels to change shape and absorb or release water [127]. A hydrogel that may be made to react to temperature changes by expanding when heated and contracting when cooled is one example. Hydrogels used in 4D-bioprinting include biopolymers such as alginate and hyaluronic acid, which can undergo significant changes in form [128]. These materials are excellent choices for bioengineering and drug delivery systems that require precise control over release profiles, as their response times can range from minutes to hours [16]. Additionally, the malleability of hydrogels allows them to adapt to various settings, enabling the creation of adaptive structures that meet each patient’s specific treatment needs. Hydrogels may be precisely molded and programmed to respond in real time to temperature or moisture changes utilizing 4D-printing technology [5]. In bioinspired engineering, for instance, a hydromorphic hydrogel might be designed to fold or unfold in response to variations in humidity, mimicking the natural behavior of plants.

4.1.3. Multi-Responsive Materials

The development of multi-responsive materials has allowed 4D-printed structures to react to a wide range of stimuli, increasing their potential applications and utility [129,130]. By adding various fillers and altering the chemical composition of the base polymers, hydrogel composites with complex behaviors in response to variations in light, moisture, or temperature can be created. For example, acrylate-based hydrogels can respond to heat and light, making them valuable in advanced bioengineering. These materials experience transformations that typically take minutes to hours, a crucial aspect of 4D-bioprinting [131]. This responsiveness is ideal for developing systems that need to be adaptive and flexible in various situations. By designing distinct meso-structures within 4D-printed objects, researchers can create responsive systems that react differently based on the spatial arrangement of materials, resulting in desirable motions when stimulated by diverse stimuli [15,132].

4.1.4. Metal and Ceramic Composites

Though responsive metal and ceramic composites are becoming more and more popular, hydrogels and polymers still dominate discussions about 4D-printing [133]. When subjected to magnetic or thermal stimuli, these materials can exhibit remarkable mechanical properties in addition to their controlled shape-changing capabilities. The majority of alloys that show shape memory effects in ceramics and metals can alter their phase state in reaction to temperature variations [134,135]. Composites such as shape memory alloys, which can revert to their original shape in response to changes in temperature or magnetic fields, exemplify these mechanisms. These materials are particularly valuable in the biomedical sector, where traditional polymers may lack the necessary mechanical strength or thermal stability [136]. High-performance applications demand reliable and rapid switching behaviors, and these composites can often respond within seconds to minutes. Their responsiveness may be further enhanced by adding particular microstructures and components, creating new opportunities in domains where traditional polymers would not be appropriate, such as biomedical engineering.

4.1.5. Biopolymer-Based Smart Materials

Biopolymers like chitosan, gelatin, and alginate have been employed more often in 4D printing due to their functional versatility and biocompatibility [137]. Because they often possess properties that enable them to react to biological environments, natural materials are appealing for use in medical applications. 4D-bioprinting is an ideal application for these materials, as they can respond to physiological changes, including variations in pH or the presence of specific proteins [74]. This reactivity enables the development of targeted drug delivery systems and promotes tissue engineering techniques that align with the dynamic biological environment [138]. With reaction durations ranging from minutes to days, adaptive applications utilizing these biopolymer-based materials can enhance regenerative medicine therapies by effectively simulating biological processes [139]. Research in this area is the only way to create new focused therapy strategies.

Table 3. Mechanisms of responsive materials in 4D-printing.

Mechanism	Description	Stimuli	Time Factor	Applications	References
Shape Memory Polymers (SMPs)	Polymers (e.g., polyurethane) that return to a preset shape when triggered by temperature or electromagnetic fields.	Temperature, electromagnetic fields.	Change occurs within seconds to minutes.	Soft robotics, biomedical devices, dynamic shape changes.	[140,141]
Hydrogels	Polymers (e.g., alginate and hyaluronic acid) that swell or shrink in response to temperature, pH, or humidity, enabling shape change.	Temperature, pH, ionic strength, humidity.	Response time varies from minutes to hours.	Bioinspired engineering, drug delivery systems, adaptive structures.	[142,143]
Multi-Responsive Materials	Materials (e.g., acrylate-based hydrogels) that react to multiple stimuli for complex behaviors and transformations.	Temperature, light, moisture.	Transformations over minutes to hours.	Advanced bioengineering applications, responsive systems with versatile functions.	[144]
Metal and Ceramic Composites	Composites (e.g., alloys) with shape memory properties that respond to thermal or magnetic stimuli.	Thermal, magnetic.	Changes typically occur over seconds to minutes.	Aerospace applications, biomedical engineering where polymers may not suffice.	[145]
Biopolymer-based Smart Materials	Biopolymers (e.g., alginate and gelatin) react to pH and biological changes for specific applications.	pH changes, biomolecule presence.	Response time varies from minutes to days.	Drug delivery, tissue engineering applications, targeted therapy strategies.	[146,147]

Table 3. Mechanisms of responsive materials in 4D-printing.

Mechanism	Description	Stimuli	Time Factor	Applications	References
Shape Memory Polymers (SMPs)	Polymers (e.g., polyurethane) that return to a preset shape when triggered by temperature or electromagnetic fields.	Temperature, electromagnetic fields.	Change occurs within seconds to minutes.	Soft robotics, biomedical devices, dynamic shape changes.	[140,141]
Hydrogels	Polymers (e.g., alginate and hyaluronic acid) that swell or shrink in response to temperature, pH, or humidity, enabling shape change.	Temperature, pH, ionic strength, humidity.	Response time varies from minutes to hours.	Bioinspired engineering, drug delivery systems, adaptive structures.	[142,143]
Multi-Responsive Materials	Materials (e.g., acrylate-based hydrogels) that react to multiple stimuli for complex behaviors and transformations.	Temperature, light, moisture.	Transformations over minutes to hours.	Advanced bioengineering applications, responsive systems with versatile functions.	[144]
Metal and Ceramic Composites	Composites (e.g., alloys) with shape memory properties that respond to thermal or magnetic stimuli.	Thermal, magnetic.	Changes typically occur over seconds to minutes.	Aerospace applications, biomedical engineering where polymers may not suffice.	[145]
Biopolymer-based Smart Materials	Biopolymers (e.g., alginate and gelatin) react to pH and biological changes for specific applications.	pH changes, biomolecule presence.	Response time varies from minutes to days.	Drug delivery, tissue engineering applications, targeted therapy strategies.	[146,147]

4.2. Potential Applications in Sustained Drug Delivery

A cutting-edge biofabrication method that allows drug delivery systems to dynamically change in response to specific stimuli is 4D-bioprinting, which incorporates time as a fourth dimension [80,148]. A more personalized, regulated, and focused approach to treatment is now possible because of this innovative approach to long-term pharmaceutical distribution [149]. Figure 4 illustrates the functional framework of the technology, highlighting the stimuli-responsive behavior, activation mechanisms, and practical biomedical applications of 4D-bioprinting. Smart materials, printing platforms, activation mechanisms, and external stimuli serve as four pillars supporting the 4D-printing paradigm. Cures such as heat, magnetic fields, chemicals, mechanical forces, light, or water are essential for printed objects to change shape or function and respond in real time to their environment. Smart materials (such as hydrogels, polymers, or shape memory composites) can react to stimuli in a predetermined manner or even autonomously after printing [150]. While the activation mechanism governs dynamic responses over time, the printing platform is crucial for ensuring the spatial arrangement of these intelligent materials according to the intended architecture.

The external applications demonstrate the practical implications of this interaction. For instance, self-folding structures for vascular tissue engineering use thermally or chemically induced folding to create perfusable blood vessels within tissue scaffolds [151]. Self-foldable sheet structures illustrate the transformation of flat designs into 3D forms, enabling deployable patches or implants that aim to reduce surgical invasiveness [152]. The defect-filling cardiac patch shows how 4D-bioprinting can address congenital heart defects or myocardial infarctions. These printed patches can expand or adapt to irregular anatomical locations, making them valuable for medical applications. The implants made from water-responsive or magnetic materials can adjust to the surrounding tissue mechanics through their elastic and self-expanding nature [153]. This adaptability is crucial for developing next-generation bioelectronic interfaces and adaptive prostheses. The following section discusses the main potential applications of 4D-bioprinting in sustained drug delivery systems (Figure 4).

4.2.1. Stimuli-Responsive Drug Delivery Systems

The key selling feature of 4D-bioprinting is its ability to produce materials that can change their structure in response to variables including pH, light, temperature, and moisture. This feature in drug delivery systems can significantly enhance the regulated release of pharmaceuticals [32]. SMPs are made to change shape under specific conditions or temperatures; they are ideal for encapsulating medications. When these materials change shape, the medication can be released again. These features can be exploited to create implants that release medications when the patient needs them, which is a very good therapeutic option with minimal side effects [33].

4.2.2. 4D-Bioprinting for Drug Delivery of Personalized Medicine

Customized drug delivery systems that consider each patient’s distinct anatomy and medical history can be produced using 4D-bioprinting [154]. This knowledge will be crucial for developing new medications to treat chronic illnesses that require tailored treatments. Because bioprinting makes it possible to create flexible scaffolds, doctors may create drug delivery systems that precisely control the rate and timing of medication release to meet the needs of individual patients [155]. In reaction to localized inflammation or infection, structures might be designed to release therapeutic compounds exactly where they are needed. Diabetes patients with 4D-printed smart implants can adjust the way their medications are released based on physiological indicators. The ability to adapt to shifting physiological conditions makes it possible to administer medication more consistently, which enhances therapeutic outcomes and boosts patient adherence [21].

4.2.3. Temporal and Spatial Control of Drug Release

One of the main advantages of 4D-bioprinting is its ability to distribute medications in a controlled way that aligns with the body’s natural rhythms, enabling customized therapies [156]. By combining many stimuli-responsive materials, researchers have created constructions that may be programmed to alter medication release in response to particular events (such as inflammation or temperature changes). Dynamic drug release profiles that adjust release patterns without further patient intervention may result from this. Multiple therapeutic agents or drugs can be administered on a single 4D-bioprinted platform because of materials with multiple reactions [157,158]. Due to this complexity, combination therapy can be delivered more effectively, allowing for the simultaneous or sequential delivery of numerous drugs in response to the body’s needs [159].

4.2.4. Tissue Engineering and Regenerative Medicine

Long-term drug administration combined with tissue engineering has significant promise for promoting tissue regeneration and healing. 4D-bioprinted scaffolds combined with pharmaceuticals can be used to support tissue regeneration while delivering growth factors, antibiotics, or anti-inflammatory treatments. These scaffolds can help promote healing while preventing infections and inflammation by synchronizing the release of therapeutic chemicals with the natural healing processes of the targeted tissue. Smart bandages allow for the real-time direct delivery of medications to wound sites by using polymeric materials that can respond to variations in pH or moisture. By actively delivering medications to the wound area, these bandages promote healing and lower the risk of infection.

4.2.5. Overcoming Limitations of Conventional Drug Delivery Systems

Traditional drug delivery technologies have two issues: inconsistent release rates and inefficient site targeting [160]. 4D-bioprinting addresses both of these difficulties. 4D-bioprinting technologies enhance traditional encapsulation techniques by making it easier to create drug carriers with complex designs, improving drug stability and release properties. By lowering dosages and increasing pharmaceutical efficacy, this tactic lowers the possibility of adverse effects [161].

The versatility of 4D-bioprinting makes it possible to quickly build personalized treatment alternatives [162]. With the use of rapid prototyping technology, tailored drug delivery systems can be developed, tested, and put into use more quickly, satisfying patient needs and reducing treatment delays [163,164]. The application of 4D-bioprinting in sustained drug delivery systems has the potential to revolutionize bioengineering, pharmacology, and medicine. By utilizing the unique properties of responsive materials, 4D-bioprinted structures have the potential to significantly improve patient outcomes and therapeutic efficacy. Future healthcare could be transformed by highly customized, efficient, and adaptable treatment modalities made possible by the incorporation of 4D-printing techniques into clinical practice, which is an exciting area of research [165].

4.3. Strategies for Enhancing Drug Delivery Efficacy

4D-bioprinting technology creates innovative medication delivery systems that may dynamically alter their properties and functionality in response to external stimuli by fusing time-responsive capabilities with 3D-printing principles [166]. This feature has the potential to greatly boost the efficacy of pharmaceutical delivery, leading to better therapeutic outcomes, fewer side effects, and higher patient compliance. The methods that use 4D-bioprinting to enhance drug delivery systems are described here [167].

4.3.1. Stimuli-Responsive Materials

In 4D-bioprinting, the utilization of stimuli-responsive materials is crucial. These materials respond to environmental conditions such as light, pH, temperature, and magnetic fields, allowing for controlled medication release. SMPs are a common material choice due to their shape memory capabilities. This implies that in response to a particular stimulus, they can revert to their initial shape. Temperature-responsive SMPs can be used to develop drug carriers that release their payload when the body temperature rises, offering a more individualized therapy approach, for example, during fever or localized inflammation.

Hydrogels can be made to expand or contract in response to variations in pH or ionic strength. Systems that release drugs in reaction to changes in the local environment, such as at the site of an infection or tumor, can be developed by carefully building hydrogels with drug-loading capabilities using 4D-bioprinting. For example, 4D-printing with chemically responsive hydrogels can allow for on-demand drug release to enhance therapeutic efficacy.

4.3.2. Customization of Drug Release Profiles

4D-bioprinting allows for the development of drug delivery systems with variable re-release patterns by adjusting the material properties and physical structure of the printed components [168]. Multi-layered structures made possible by 4D-bioprinting can hold several drugs that, depending on the local environment, can be programmed to release either concurrently or sequentially. For combination medicines, this approach is perfect since it allows for selecting between immediate and extended release for active pharmaceutical ingredients (APIs) [169].

Researchers can modify the porosity of bioprinted objects to alter the drug diffusion rates. Materials having a larger porosity can release drugs faster, whereas materials with a denser structure can hold onto drugs longer and release them later [170]. This approach enables the system to be fine-tuned in accordance with specific treatment requirements.

4.3.3. Integration of Targeting Mechanisms

Targeted approaches increase therapeutic efficacy and decrease systemic side effects by better localizing drug delivery [171]. Targeted medication delivery is possible by enhancing bioprinted drug carriers with ligands or antibodies that attach to receptors expressed in tumors or target organs. This targeting capability allows for the precise localization of drug-loaded particles, resulting in increased therapeutic effectiveness. 4D-printed cancer treatment structures can provide targeted drug release at the tumor site by including ligands that bind to cancer cell receptors.

Using magnetic nanoparticles in drug delivery systems enables targeting with a magnetic field. Therapeutic medications can be precisely localized by employing a magnetic field to attract the drug-loaded structures to certain locations [172]. 4D-bioprinting has the potential to produce magnetically responsive, individualized structures that may actively guide and deliver drugs to certain parts of the body [173].

4.3.4. Enhancing Biocompatibility and Functional Integration

Biocompatible materials must be incorporated into 4D-printed structures to guarantee that the medication delivery system is well-tolerated by the body [174]. Biopolymers such as alginate, chitosan, or gelatin are utilized to ensure that the printed structures are compatible with biological systems. By altering these materials to increase their bioactivity or mechanical properties, the drug delivery system may be even more successful [175].

4D-bioprinting has made it feasible to employ living cells in drug delivery scaffolds. These cells may have a role in the metabolism and conversion of medications, which could improve their therapeutic impact and enable them to react to physiological stimuli in a dynamic manner [176]. For instance, embedding cells in hydrogels can result in systems that release drugs and generate growth factors or signaling molecules that encourage tissue regeneration.

4.3.5. Developing Personalized Drug Delivery Systems

The development of customized medical solutions to satisfy each patient’s particular needs is made possible by the amazing customization potential of 4D-bioprinting [177]. With 4D-bioprinting, patient-derived data (such as genetic or imaging data) can be used to develop customized medication delivery systems that are suited to certain anatomical configurations or disease states [178]. Because drug release is personalized, it is more precise, which improves therapeutic efficacy.

4D-bioprinted structures can be customized to meet the specific requirements of each patient in addition to reacting to environmental stimuli [179]. The ability to alter a medication’s release according to a patient’s metabolic state is an example of a printed polymer that may dynamically adjust to their biochemical changes [180]. 4D-bioprinting has the potential to enhance the effectiveness of medication delivery in numerous ways. 4D-bioprinting is revolutionizing innovative drug delivery strategies, as summarized in

Table 4. Strategies for enhancing drug delivery efficacy by advanced materials.

Strategy	Mechanism	Materials	Significance	Limitations	Refs.
Stimuli-Responsive Materials	React to stimuli (pH, temperature) for controlled release.	Shape memory polymers (SMPs), hydrogels.	Enables precise drug release timing and dosage.	Variable response times can affect predictability.	[102,181]
Customization of Drug Release	Tailors’ profiles based on local conditions.	Bioprinted components with porosity.	Aligns with patient-specific needs, reducing side effects.	Designing multi-layered structures can be complex.	[16,182]
Integration of Targeting Mechanisms	Uses ligands and magnetic nanoparticles for localization.	Ligand-enhanced carriers, magnetic nanoparticles.	Increases efficacy by minimizing systemic exposure.	Design complexity due to need for suitable ligands; potential off-target effects.	[16,182]
Enhancing Biocompatibility	Uses biopolymers and living cells for active therapy.	Alginate, chitosan, gelatin.	Promotes better acceptance and integration in biological systems.	Biocompatibility does not ensure full efficacy; risks in cellular viability.	[183,184]
Developing Personalized Systems	Customizes systems to fit individual patient needs.	Patient-derived materials, customizable polymers.	Enhance treatment accuracy for better outcomes.	High costs and design time may limit adoption.	[185]

. In order to optimize drug release patterns, integrate targeting mechanisms, guarantee biocompatibility, and provide customized solutions, this technique makes use of responsive materials. These systems have the potential to transform therapeutic approaches and lead to better results for a variety of medical problems as long as research continues to advance.

5. Future Directions and Challenges for Drug Delivery by 4D-Bioprinting

An innovative approach to drug delivery systems is provided by 4D-bioprinting, which leverages the spatiotemporal evolution of stimuli-responsive materials [80]. Although this technology holds great promise for enhancing drug delivery efficacy, it must overcome some challenges before its therapeutic uses can be completely realized [74]. This section examines the current barriers to the development of 4D-bioprinting for drug delivery as well as possible future avenues for this study. It is crucial to perform research on novel bioinks that exhibit enhanced sensitivity to specific environmental conditions, including light, pH, temperature, magnetic fields, and others. It is also important to learn about innovative hybrid bioinks that combine natural and synthetic polymers to improve mechanical properties and responsiveness.

Future research should focus on structures made of multiple stimuli-responsive materials that can respond in concert [186]. By developing complementary bioinks, researchers may construct systems that can manage complex and variable drug release profiles. Thanks to developments in computer modeling and imaging technology, 4D-bioprinting may allow us to develop customized drug delivery systems that are tailored to the architecture and pathological conditions of each patient. This allows for the fine-tuning of side effect profiles and therapeutic efficacy [187].

4D-printed drug delivery devices that predict how patients would respond to different medicine formulations using artificial intelligence (AI) and machine learning algorithms may provide a more individualized approach to therapy [188,189]. Research will focus on improving the surface characteristics and architecture of 4D-bioprinted devices in order to obtain precise control over drug re-release kinetics [190]. By altering elements like pore size and material composition, drug release behavior can be tailored to each patient’s unique treatment needs.

By creating 4D-bioprinted systems that can distribute many medications simultaneously or in a staggered manner, resulting in synchronized therapeutic activity, the difficulties associated with combination medications, which are frequently used to treat cancer and chronic illnesses, may be addressed [191]. 4D-bioprinting has the potential to revolutionize the assessment of medication toxicity and efficacy by producing complex tissue models that closely mimic physiological conditions. These bioprinted models can aid in high-throughput drug screening and personalized treatment, ultimately reducing the need for animal drug testing [192].

4D-printing and organ-on-a-chip technology can be used to construct a micro physiological system that replicates the responses of a human organ [193]. Drug testing can make use of these technologies, which provide a more accurate and regulated environment for learning about pharmacokinetics and dynamics. Future collaboration between companies and researchers is essential to developing comprehensive quality control guidelines and regulatory frameworks specific to 4D-bioprinted systems and materials [194]. For these innovative technologies to successfully enter clinical settings, regulatory clarity is essential.

More collaboration between researchers, regulators, and industry participants is necessary to advance 4D-bioprinting technology [195,196]. This is particularly true when it comes to developing guidelines for the efficacy and safety of innovative materials and drug delivery systems. The practical use of currently available stimuli-responsive materials is frequently hampered by mechanical properties, stability in physiological conditions, and controlled release mechanisms. More research is needed to develop materials that maintain their structure over extended periods of time while still displaying the desired reaction [197].

The complex mechanisms of the human biological system are extremely difficult to replicate. It is important to gain a deeper comprehension of tissue dynamics and response mechanisms, which are significantly impacted by drug delivery outcomes brought about by interactions between cells, extracellular matrices, and the entire biophysical environment [198]. There is still work to be carried out to scale up 4D-bioprinting techniques successfully and efficiently without compromising quality. The creation of affordable, expandable production techniques that preserve high levels of functionality and accuracy is essential to the successful commercialization of 4D-bioprinting technology [199].

Like any new medical technology, the ethical issues around 4D-bioprinting need to be thoroughly investigated [25]. It is necessary to address issues with patient consent, data privacy, and potential misuse of bioprinted goods. Clear regulatory pathways must be established for the clearance of 4D-bioprinted medication delivery devices before they can be used in clinical settings [16]. There may be opposition to incorporating 4D bioprinting processes and products into existing healthcare systems since it will be essential to reassess current treatment regimens and train healthcare personnel. We must educate people and transition to technology-driven, customized medicine in order to address these challenges.

A chronology of 4D-bioprinting development is shown in Figure 5, starting with improvements in fundamental materials and ending with complex computational integration. The upward structure represents the anticipated increase in system complexity and technological capabilities in later iterations. Future 4D-printing will utilize composite reinforcements, shape-memory materials, and smart polymers. These materials will be optimized for mechanical strength, reactivity, and functional performance to meet specific physiological requirements [134]. The next step in enhancing the accuracy and versatility of printed structures is to incorporate systems that respond to various stimuli, such as heat, magnetism, pH, and light. This will enable programmable shapes and more precise modifications. This step is crucial for creating biomimetic structures that can adapt to their environment. AI is expected to play a key role in identifying structural defects, automating bioprinting processes, and enabling self-regulation in printed structures [200]. By improving reliability and reproducibility while reducing the need for human intervention, these advancements will facilitate the creation of clinical-grade intelligent tissue constructs.

A significant area of research involves transitioning 4D-printing from experimental environments to commercially viable products [201]. Successful integration of 4D-printed tissues and devices into clinical and industrial settings will require high-throughput additive printing techniques for process monitoring and large-scale production strategies [202]. The pinnacle of this trajectory will be the use of AI-driven simulation and predictive modeling, which will transform design optimization, failure prediction, and functional customization [203]. Computational frameworks will enable real-time modeling of dynamic material responses, significantly reducing trial-and-error in experimental setups.

6. Conclusions

Although biopolymers have advanced significantly in 4D-bioprinting, numerous challenges remain. To guarantee consistency in printability, mechanical fidelity, and biological performance, the biopolymers used must be meticulously optimized. Future research should focus on developing multifunctional biopolymers that have enhanced mechanical properties and biological interaction, similar to the intricate extracellular matrix of target tissues. The concepts of responsive materials utilized in 4D-printing open up new possibilities for this technology, from soft robotics to medical devices. Researchers have used shape memory polymers, hydrogels, composites, and biopolymers to create structures that can adapt to their environment and function similarly to biological systems. These materials will become even more dynamic as 4D-printing and material science advance, leading to new and creative applications in technology and medicine. The future of 4D-bioprinting in drug delivery holds exciting new possibilities for personalized treatment, innovative drug release methods, and sophisticated testing models. If researchers and industry stakeholders address the present problems with materials, complexity, scalability, and ethical considerations, the full potential of this groundbreaking technology can be fulfilled. With the ongoing advancements in 4D-bioprinting and the collaboration between the biotech and pharmaceutical sectors, it is anticipated that therapeutic efficacy and patient care will experience significant improvements.