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Review

Polydopamine Nanocomposite Hydrogel for Drug Slow-Release in Bone Defect Repair: A Review of Research Advances

1
Department of Clinical Pharmacy, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi 563006, China
2
Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563006, China
3
Key Laboratory of Clinical Pharmacy of Zunyi City, Zunyi Medical University, Zunyi 563006, China
4
Cancer Research UK Manchester Institute, The University of Manchester, Cheshire SK10 4TG, UK
*
Author to whom correspondence should be addressed.
Gels 2025, 11(3), 190; https://doi.org/10.3390/gels11030190
Submission received: 16 February 2025 / Revised: 27 February 2025 / Accepted: 4 March 2025 / Published: 8 March 2025
(This article belongs to the Special Issue Hydrogel for Sustained Delivery of Therapeutic Agents (2nd Edition))

Abstract

In recent years, hydrogels have emerged as promising candidates for bone defect repair due to their excellent biocompatibility, high porosity, and water-retentive properties. However, conventional hydrogels face significant challenges in clinical translation, including brittleness, low mechanical strength, and poorly controlled drug degradation rates. To address these limitations, as a multifunctional polymer, polydopamine (PDA) has shown great potential in both bone regeneration and drug delivery systems. Its robust adhesive properties, biocompatibility, and responsiveness to photothermal stimulation make it an ideal candidate for enhancing hydrogel performance. Integrating PDA into conventional hydrogels not only improves their mechanical properties but also creates an environment conducive to cell adhesion, proliferation, and differentiation, thereby promoting bone defect repair. Moreover, PDA facilitates controlled drug release, offering a promising approach to optimizing treatment outcomes. This paper first explores the mechanisms through which PDA promotes bone regeneration, laying the foundation for its clinical translation. Additionally, it discusses the application of PDA-based nanocomposite hydrogels as advanced drug delivery systems for bone defect repair, providing valuable insights for both research and clinical translation.

1. Introduction

Bone defects due to trauma, infection or osteoporosis pose a substantial challenge to the global healthcare system, affecting over 20 million patients annually [1,2,3]. Currently, autologous and allogeneic bone grafts remain the gold standard for the treatment of bone defect repair, but other repair strategies are necessary due to high donor site morbidity, limited availability, and immune refractory reactions [4,5]. In addition, effective bone repair requires sustained pharmacological activity to promote osteoblast proliferation and bone regeneration, a requirement that synthetic implants and systemic drug therapies often fail to meet due to issues of malintegration, off-target toxicity, and inadequate control over osteogenic factor delivery [6,7,8]. As a result, there is an urgent need to develop a drug delivery system with excellent slow-release properties to enhance bone repair and overcome the limitations of existing treatment options. Combining osteogenic drugs with biocompatible and biodegradable carrier materials can create a system that ensures effective loading and controlled release of drugs, thereby sustaining therapeutic action at the defect site and enhancing efficiency while minimizing systemic side effects [9].
Hydrogel shows unique advantages in bone tissue engineering due to its three-dimensional hydration network and extracellular matrix (ECM)-like microenvironment [10,11,12]. It not only has good biocompatibility but also effectively promotes bone regeneration by supporting cellular infiltration, facilitating nutrient diffusion, and enabling local drug delivery [13,14,15]. However, conventional hydrogels often lack the mechanical elasticity and dynamic responsiveness required for load-bearing applications or controlled therapeutic release [16,17,18]. These challenges have led researchers to work on the development of enhanced hydrogels to optimize their mechanical elasticity and dynamic responsiveness to meet the clinical needs of bone regeneration.
Inspired by the adhesive properties of marine mussels, polydopamine (PDA)—a dopamine-based polymer—has emerged as a promising material in the development of advanced hydrogels and bone tissue engineering [19,20]. PDA is formed through the spontaneous polymerization of dopamine monomers under alkaline conditions. Its formation mechanism involves multiple pathways, including both noncovalent self-assembly and covalent polymerization [21] (Figure 1). Initially, dopamine is oxidized to dopamine quinone (DQ), which undergoes cyclization and rearrangement to produce intermediates such as 5,6-dihydroxyindole (DHI) and indole quinone. These intermediates are further polymerized to form oligomers, ultimately producing PDA [21,22]. The resulting polymer is rich in catechol groups, which confer several functional properties, as follows: (i) strong interfacial adhesion, allowing stable binding to both organic (e.g., hydrogels, peptide copolymers) and inorganic (e.g., metal and silicon-based) substrates, facilitating composite material design [23,24,25]; (ii) photo-thermal responsiveness, as the conjugated single-double bonds in its structure enable significant near-infrared (NIR) absorption and efficient photothermal conversion, enabling remote drug release and antimicrobial effects [26,27,28,29]; and (iii) multifunctional modification potential, with abundant amine, imine, and aromatic ring structures that facilitate efficient drug loading and targeted delivery via chemical reactions or π-π stacking [30,31,32,33]. Additionally, PDA’s antioxidant and immunomodulatory properties, such as promoting macrophage M2 polarization, contribute to a pro-regenerative microenvironment for bone repair, enhancing osteogenesis and angiogenesis [34,35]. The diverse nanostructural forms of PDA—such as nanosheets [36], nanoparticles [37], nanocapsules [38], and mesoporous PDAs [39]—offer high modification flexibility, optimizing drug delivery and bone repair effectiveness. Figure 2 illustrates how different PDA structures integrated with hydrogels enable controlled drug release in bone defect repair, regulate inflammation, and promote bone and vascular remodeling. These attributes make PDA a key component in enhancing the mechanical properties and bioactivity of hydrogels, providing a novel approach for developing a smart, responsive platform for bone repair.
Despite significant research on PDA-based nanocomposite hydrogels, current reviews often focus on the physicochemical properties of PDA, with less emphasis on its role in bone repair mechanisms or a systematic classification of PDA hydrogel composites. This paper aims to bridge this gap by delineating the molecular and cellular mechanisms through which PDA promotes bone regeneration, including macrophage polarization, angiogenesis, and Runx2-mediated osteogenesis. It provides a comprehensive classification of PDA-based nanocomposite hydrogels, highlighting design principles, drug loading strategies, and preclinical outcomes. The paper also identifies challenges in clinical translation, such as polymerization variability and long-term biocompatibility, and suggests directions for materials optimization. By integrating materials science with orthopedic application, this study seeks to expedite the development of PDA hydrogels as a versatile platform for bone defect repair. With this comprehensive review, we hope to pave the way for future research and clinical applications of PDA nanocomposite hydrogels in bone defect repair.

2. Application and Function of PDA in Bone Defect Repair

A variety of organic and inorganic nanodrug delivery systems have been developed for the treatment of bone diseases, such as silica nanoparticles, gold nanoparticles, calcium phosphate nanoparticles, chitosan nanoparticles, liposome nanoparticles, and polymer nanoparticles [40,41]. However, these systems still face some important limitations, including low drug loading, limited physiological compatibility, poor degradability, and too fast drug release rates [42,43]. To address these drawbacks, PDA has gradually attracted widespread attention as an adjunctive drug delivery system in recent years. PDA not only significantly enhances drug loading capacity, but also improves drug delivery by increasing cell capture efficiency. In addition, PDA itself has a photothermal effect, which can respond to the stimulation of an external light source and thus regulate drug release. In addition, PDA can promote cell adhesion and regulate cell differentiation, which makes it a material with wide application potential in the treatment of orthopedic diseases. Studies have gradually revealed [44,45,46] the multifaceted functions and mechanisms of PDA in bone regeneration, and that it can provide favorable conditions for bone tissue repair by altering the microenvironment, regulating the immune response, and promoting the proliferation and differentiation of osteoblasts.
In this section, we will focus on the different functions of PDA in promoting bone regeneration, especially how it can be further developed in bone defect repair through photothermal effects, cell adhesion enhancement, and regulation of differentiation.

2.1. Anti-Inflammation

The inflammatory response plays a crucial role in physiological processes such as tissue injury and bone defect repair. On the one hand, angiogenesis triggered by immune inflammation contributes to the promotion of bone regeneration. Therefore, excessive suppression of early inflammation may interfere with angiogenesis, thereby affecting the healing process of bone defects [47,48]. On the other hand, excessive immune inflammatory response may lead to localized granulomas and fibrous encapsulation, which in turn prevents stable fixation of the implant [49,50]. For this reason, balancing the intensity and duration of the inflammatory response during bone defect repair is crucial for promoting bone healing. The aromatic ring structure and hydrophilic catechol groups on the surface of PDA have antioxidant properties, which can scavenge free radicals in the body and alleviate oxidative stress, thus reducing the inflammatory response triggered by oxidative stress. Through this antioxidant mechanism, PDA helps to improve the local immune environment during bone repair and promotes the osteogenesis process [51,52,53]. In addition, in the local inflammatory region, PDA can reduce the activity of inflammatory cells and the release of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, through its unique photothermal effect, thus controlling the inflammatory response and preventing the adverse effects of excessive inflammation on bone tissue repair [54]. At the same time, PDA can also promote macrophage M2 type polarization, thereby creating an immune microenvironment conducive to bone repair [48]. Li et al. [55] showed that PDA could inhibit NF-κB expression by increasing i -кB expression in macrophages, thereby reducing the inflammatory response induced by implants.

2.2. Promoting Cell Adhesion and Proliferation

PDA can promote cell adhesion through several mechanisms. First, the amine and catechol groups in PDA can strongly chelate with calcium ions (Ca2+). This chelation promotes the interaction of blood Ca²⁺ with phosphate ions (PO43−), which in turn precipitates and forms a mineralized coating on the PDA surface [52,56]. This mineralization process not only enhances the bioactivity of the material but also provides an ideal surface for osteoblasts and promotes cell attachment and proliferation. Meanwhile, a calcium phosphate crystal is deposited on the surface of PDA, which usually shows a coral like or amorphous nanohemispherical structure [57,58]. This amorphous calcium phosphate is a precursor for the formation of biogenic bone-like apatite (i.e., the inorganic component of bone), which plays an important role in bone repair [59,60]. Studies have shown that, on PDA surfaces containing calcium phosphate, osteoblasts are able to form larger cell clusters. In contrast, on smooth, pure PDA surfaces, osteoblasts show a tendency to diffuse and have difficulty aggregating. This shows that the rough structure of the mineralized coating on the surface of PDA and the formation of the mineralized layer have a facilitating effect on the adhesion and aggregation behavior of osteoblasts [61].
Secondly, PDA, through its surface hydrophilicity and chemical reactivity, can promote the production of a large number of extracellular matrix (ECM) proteins, such as collagen, fibronectin, and vitronectin, by cells. Binding of integrin receptors on cells to these extracellular matrices can activate intracellular signaling pathways (e.g., FAK signaling pathway) to further regulate cellular value addition and differentiation [62,63,64]. In addition to exhibiting changes in cell adhesion capacity, it was found that cells cultured on the PDA surface showed a significant increase in the number of cells in the S phase and a decrease in the number of cells in the sub-G1 phase. This suggests that the PDA-coated material has a promotional effect on cell proliferation [65]. In summary, PDA not only promotes cell adhesion, but also promotes the mineralization process by regulating cell proliferation, promoting osteogenic differentiation, and through interaction with minerals such as calcium phosphate. This provides an ideal support platform for bone defect repair.

2.3. Promoting Osteogenesis and Angiogenesis

It has been found that bone tissue is rich in dopaminergic neurons and expresses various DA receptors [34,44]. These receptors, categorized into five types (D1 to D5) [66,67,68], play critical roles in cellular signaling and regulating numerous physiological processes. PDA materials feature dopamine-related reactive groups on their surfaces, enabling interactions with dopamine receptors on cell surfaces, thereby influencing cellular behavior and responses. In bone tissue, the regulation of the extracellular signal regulated kinase (ERK) signaling pathway significantly affects osteoblast behavior. Wang et al. [69] identified D1 as a specific target through which dopamine promotes osteogenic expression by enhancing ERK phosphorylation. This phosphorylation increases the transcriptional activity of RUNX2, a key osteogenic transcription factor that directly drives osteogenic differentiation. The activity of this pathway may also vary depending on the cell type involved. Furthermore, the dopamine D1 receptor (D1R) regulates osteogenic signaling and promotes bone regeneration by activating signaling pathways such as the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP responsive element binding protein (CREB) pathway [34,70,71]. The coordinated activity of osteoblasts and osteoclasts is crucial during the later stages of bone repair, maintaining the balance necessary for bone tissue health and reconstruction. Osteoblasts facilitate the formation of new bone, while osteoclasts mediate bone resorption, with their interaction ensuring proper bone metabolism. Excessive bone resorption, however, may lead to osteoporosis, potentially compromising bone repair effectiveness. While findings on PDA’s regulation of osteoblast activity remain inconsistent, some studies suggest it may be closely linked to the local degradation concentration of PDA, a relationship that requires clarifying through further investigation [72].

3. Advances in the Application of PDA-Hydrogel Based Drug Slow Release System in the Repair of Bone Defects

PDA-based nanocomposite hydrogels, particularly in controlled drug delivery, have driven significant advancements in bone defect repair. These hydrogels are composed of both synthetic and natural polymers. Common synthetic polymers include polyacrylic acid and its derivatives, poly(vinyl alcohol), poly(vinyl oxide), poly(acrylamide), and self-assembling peptides. Natural polymers typically used are collagen, gelatin, hyaluronic acid, alginate, and chitosan. The fabrication of PDA-based hydrogels involves diverse and complex methods, such as hydrogels with dopamine (DA) side-chain branches [73,74,75], hydrogels loaded with PDA nanoparticles (NPs) [76,77,78], and hydrogels incorporating PDA-modified nanomaterials [79,80,81,82]. These hydrogels, including chitosan, gelatin, PEG, and peptides, are often functionalized with PDA to enhance their adhesion properties and bioactivity, offering novel solutions for bone defect repair and laying the groundwork for clinical application (Figure 3). This review explores the unique properties of PDA and examines its integration with various hydrogel types, highlighting several representative composite hydrogels from recent studies (Table 1).

3.1. Composite Nanohydrogels of Natural Materials with Polydopamine Nanostructures

Natural polymers are highly favored in bone defect repair due to their superior biocompatibility and biodegradability. However, their hydrogels often lack adequate mechanical properties, limiting clinical applications. Incorporating polydopamine (PDA) into these hydrogels can significantly improve their mechanical attributes and functional capabilities, making them excellent candidates for drug delivery in bone defect repair.

3.1.1. Chitosan-Based PDA Hydrogel

Chitosan, a natural polysaccharide, is widely recognized as an ideal biomaterial for hydrogel preparation due to its excellent biocompatibility, cell adhesion properties, and versatile applications in drug delivery and tissue engineering [134,135]. However, it has limitations, such as poor mechanical strength and instability in high-humidity or acidic environments [136,137]. Incorporating polydopamine (PDA) significantly enhances the functionality of chitosan hydrogels, expanding their potential in biomedical and smart material applications [138,139,140]. These interactions improve the mechanical properties of the hydrogel, increasing stiffness and toughness while reducing swelling and overcoming the mechanical degradation and adhesion loss typically observed in chitosan hydrogels due to their high hygroscopicity [141,142,143]. Additionally, while conventional chitosan hydrogels are often prepared under acidic conditions, their pH stability is limited, and acidic environments can harm bioactive components [144]. Cross-linking with PDA creates a stable network on the chitosan surface, improving water stability and allowing the hydrogel to maintain integrity under acidic or humid conditions, while also enhancing thermal stability [145]. Moreover, PDA-modified chitosan hydrogels offer improved drug delivery capacity by forming a dense network structure that prolongs drug release and enables controlled, slow-release effects [146,147]. The combination of PDA and chitosan not only addresses the limitations of traditional chitosan hydrogels but also advances the development of smart-responsive biomaterials [148]. To further enhance the osteogenic potential, bioactive molecules, mineral particles, or nanomaterials such as hydroxyapatite, silica gel, or calcium–phosphorus complexes can be incorporated.
Rahnama et al. [149] developed an injectable hydrogel combining chitosan, dopamine, and inositol aldehyde for drug delivery. The hydrogel rapidly gels under physiological conditions and exhibits sustained indomethacin release across various pH environments. Its cytocompatibility with L-929 fibroblasts underscores its potential for controlled drug delivery.
Wan et al. [82] used PDA-modified hydroxybutyl chitosan hydrogels for bone repair. The hydrogels, with NIR light responsive microspheres, facilitated a sequential release of aspirin and BMP-2, aligning with the bone healing process (Figure 4). This approach offers a novel therapeutic strategy for bone-related conditions.

3.1.2. Alginate-Based PDA Hydrogel

Alginate (Alg), a hydrophilic polysaccharide derived from brown algae, is valued for its excellent biocompatibility and degradability, making it ideal for applications in wound healing, microencapsulation, drug delivery, and 3D scaffolds for bone and soft tissue engineering [150,151]. However, alginate hydrogels often suffer from low mechanical strength and slow degradation rates [152,153,154,155]. Recent studies indicate that incorporating PDA significantly enhances the biocompatibility, mechanical strength, and adhesion of alginate hydrogels, particularly in underwater environments [83,156]. PDA modification improves the mechanical and adhesive properties of the hydrogels through catechol interactions, balancing stiffness and flexibility. This enhancement not only broadens the applicability of alginate hydrogels in tissue engineering but also boosts their diffusion capabilities at contact surfaces [157]. Additionally, PDA-modified alginate hydrogels demonstrate improved cohesion, stability, drug loading capacity, and sustained release properties, offering superior drug delivery performance compared to unmodified alginate hydrogels [158,159]. In summary, alginate–PDA hydrogels provide better control over bioviscosity and osteogenic induction compared to pure alginate hydrogels.
Zhang et al. [83] modified alginate with PDA, resulting in hydrogels that promoted MSC cell survival, proliferation, and osteogenic differentiation (Figure 5). Additionally, PDA’s adhesive properties enabled the coating of silver nanoparticles on the alginate PDA gel surface, thereby conferring significant antimicrobial properties to the gel (Figure 6). This hydrogel could be a good tool to promote cell encapsulation and bone regeneration, especially for contaminated bone defects.

3.1.3. Gelatin-Based PDA Hydrogel

Gelatin, derived from the hydrolysis of collagen, is widely used in tissue engineering and drug delivery due to its biocompatibility, degradability, and cell adhesion properties [160,161]. However, gelatin hydrogels face challenges such as weak mechanical strength, poor thermal stability, and limited osteoinductivity, which hinder their effectiveness as bone repair materials [162,163,164]. Similar to chitosan and alginate, the incorporation of PDA enhances gelatin hydrogels by improving their mechanical strength, thermal stability, and cell affinity. These improvements result from noncovalent interactions, particularly those involving the catechol groups of PDA [165,166].
Chen et al. [84] prepared a bifunctional alginate (ALG)/allylated gelatin (GelAGE) hydrogel with UV and Sr2+ cross-linking, incorporating PDA particles. This hydrogel showed enhanced mechanical strength compared to other injectable hydrogels. Additionally, the inclusion of PDA@DOX particles increased porosity, facilitating cell penetration. Experimental results revealed that the ALG/GelAGE-PDA@DOX hydrogel achieved a high in vitro killing rate of MG63 cells and exhibited promising bone-like mineralization properties, indicating its potential for bone tissue regeneration.
Gan et al. [85] developed a mussel inspired bilayer hydrogel for cartilage defect repair (Figure 7). The upper layer comprises a methacrylamide polydopamine (Gel-MA-PDA) hydrogel loaded with transforming growth factor β3 (TGF-β3) to support cartilage regeneration, while the lower layer is a methacrylamide polydopamine/hydroxyapatite gelatin (GelMA-PDA/HA) hydrogel containing bone morphogenetic protein 2 (BMP-2) to aid subchondral bone repair. PDA in the lower layer facilitates hydroxyapatite mineralization, mimicking subchondral bone structure and enhancing mechanical strength. This bilayer hydrogel supports cell proliferation and differentiation, effectively delivering BMP-2 and TGF-β3 for targeted cartilage and subchondral bone regeneration.

3.2. Composite Nanohydrogels of Synthetic Materials with Polydopamine Nanostructures

3.2.1. Nanohydrogels Based on Frequently Studied Synthetic Materials

Compared to natural materials, traditional synthetic materials, such as polyethylene glycol (PEG), polyvinyl alcohol (PVA), and poly (methyl methacrylate) (PMMA), are frequently employed to construct strong hydrogels due to their cost effectiveness and robust mechanical attributes [167,168]. Despite these advantages, they typically lack the necessary biocompatibility that facilitates cell adhesion, proliferation, and differentiation. Furthermore, the degradation of polyester compounds like PLGA, PGA, and PLA within the body can result in acidic byproducts that may provoke inflammatory responses, potentially hindering bone healing [169]. The integration of (PDA) into these materials has shown promise in overcoming these limitations, thereby enhancing their utility for bone repair purposes [170,171].
Wu et al. [86] have developed a gelatin methacryloyl/poly (methyl methacrylate)/polydopamine (GelMA/PMMA/PDA) photohydrothermal gel aimed at addressing bone defects. This hydrogel underwent rigorous testing through in vitro cell culture experiments and in vivo animal studies to evaluate its biocompatibility and bone repair efficacy. The data revealed its potent osteogenic potential, marking it as a viable treatment for bone defects.
Dashtimoghadam et al. [87] utilized PLGA to create monodisperse microcarriers encapsulating VEGF, which were then functionalized with a biomimetic PDA coating to bind BMP-2. These microcarriers were integrated with an injectable alginate RGD hydrogel to facilitate the controlled release of VEGF and BMP-2 (Figure 8). The findings indicated that the PDA functionalized microcarriers not only improved the immobilization and bioavailability of BMP-2, but also enhanced the attachment and proliferation of mesenchymal stem cells (MSCs), suggesting a promising approach for stem cell therapy in bone defect treatment.
In another study, Xu et al. [105] synthesized a silver nanoparticles/PDA/PEG hydrogel, providing both antimicrobial capabilities and promoting bone mineralization. This utilized PDA mineralization on polyethylene (PEG) hydrogels, and then improved the hydrogel’s adhesion to bone tissue and biocompatibility. Experimental results demonstrated that this hydrogel promotes the proliferation and differentiation of osteoblasts, while inducing bone mineralization and offering antimicrobial protection against infections (Figure 9 and Figure 10). A recent study [27] also describes the preparation of a multifunctional gelatin methacrylate/dopamine gelatin methacrylate adhesive hydrogel coating that includes two-dimensional black phosphorus (BP) nanoparticles coated with dopamine. This multifunctional hydrogel coating, in combination with BP, facilitates photothermal mediated drug delivery and bacterial eradication through photodynamic therapy, aiding in bone healing.

3.2.2. Nanohydrogels Based on Self-Assembling Peptides

Beyond the traditional hydrogels of synthetic materials, peptide-based self-assembling hydrogels have garnered significant attention in materials science and biomedical applications in recent years [172,173]. These peptide-based supramolecular gel scaffolds are extensively utilized in cell culture, tissue engineering, drug delivery, and wound healing, thanks to their straightforward preparation, biocompatibility, and degradability. Previous studies have demonstrated that self-assembling peptide hydrogels are effective in facilitating the repair of bone and cartilage, as well as promoting wound healing [174].
Despite their utility, peptide-based hydrogels often exhibit insufficient functionality and mechanical strength [175,176]. To overcome this limitation, researchers have started to incorporate various inorganic nanomaterials and polymers into these hydrogels, creating hybrid heteropeptide hydrogels that enhance their properties. Studies have demonstrated [177,178,179] that incorporating appropriate amounts of inorganic nanoparticles can significantly improve the mechanical strength and endow new functionalities to the gels. However, achieving compatibility between certain inorganic nanomaterials and the gel matrix can be challenging. The introduction of polymers like (PNIPAAm) can enhance compatibility, but their synthesis is often complex and typically requires organic solvents, which may introduce residues that can adversely affect the biomedical properties of the gels. Therefore, developing novel hydrogel systems that are multifunctionalized and stable in physiological environments is crucial for advancing hydrogel applications in biomedicine.
In light of the mechanical and functional limitations of hydrogels, researchers have started to incorporate polydopamine into peptide hydrogels. This integration not only reduces the critical gel concentration but also significantly enhances their mechanical properties. For example, Fichman et al. [180] showed that self-polymerized dopamine can react with lysine residues in peptides, effectively tuning the viscoelastic properties of the gels (Figure 11). Their findings indicated that incorporating dopamine during gelation significantly increases the storage modulus of the peptide gel while maintaining their shear thinning recovery behavior.
Additionally, the remarkable photothermal properties of PDA have been utilized to facilitate the loading of drug carrying agents through π-π bonding, leading to the development of a therapeutic platform that integrates photothermal therapy with controlled drug release, thus achieving multifunctionality in hydrogels. For instance, Falcone et al. [181] encapsulated polydopamine nanoparticles (PDNPs) loaded with the hydrophobic drug rifampicin within a C14-FF hydrogel and used laser heating to trigger drug release (Figure 12). By adjusting the laser power and duration, precise control over the drug release rate was achieved. When the laser irradiates the polydopamine layer in the nanocomposite hydrogel, the PDA absorbs the laser energy and converts it into thermal energy, raising the temperature within the hydrogel and altering its structure to facilitate drug release. The results indicate that the C14-FF hydrogel containing PDNPs can sustain the delivery of high concentrations of rifampin after laser induction, effectively preventing bacterial growth (Figure 13). Overall, initiating peptide-based gels in the presence of dopamine offers a simple yet effective method for modulating their viscoelastic mechanical properties, with promising applications in medical wound dressings and controlled drug delivery.
While the use of dopamine self-polymerization as a technique for enhancing peptide-based gels has been proposed, there is a scarcity of detailed reports on its specific applications and effects. Moreover, research into the mechanisms of action and optimization conditions for dopamine in peptide-based gels is limited, particularly in terms of evaluating and comparing effects across different peptide systems and application scenarios. Therefore, despite its potential, the application prospects and advantages of dopamine self-polymerization in peptide-based gels require further validation through more in-depth experimental studies.

4. Conclusions and Outlook

Polydopamine (PDA)-based nanocomposite hydrogels represent a promising advancement in drug delivery, offering significant improvements over conventional hydrogels in terms of biocompatibility, drug loading capacity, mechanical strength, and controlled release capabilities. These hydrogels have diverse applications in medicine, including tissue adhesion, sealing, and hemostasis during surgical procedures. By leveraging the unique properties of PDA alongside the advantages of hydrogels, these systems can be engineered to deliver drugs in a controlled manner, often through the integration of nanoparticles or drug carriers. This approach can enhance drug stability, bioactivity, and concentration at target sites, potentially benefiting bone tissue regeneration and addressing bone defect-related conditions.
However, PDA-based hydrogels remain in the research and development stage and have not yet reached widespread commercialization. In contrast, other biomaterials such as chitosan, PEG hydrogel, and fibrin have achieved industrial-scale production, driven by advancements in synthesis, clinical trials, and regulatory approval. For PDA-based hydrogels to follow a similar path, further optimization of the synthesis process and biodegradation properties is essential to ensure consistent polymerization and batch stability, meeting the stringent regulatory standards for medical devices.
Despite their potential, PDA-based hydrogels face three main challenges: (1) limited understanding of PDA polymerization mechanisms, (2) risk of drug leakage during nanoparticle coating, and (3) dependence on cytotoxic cross-linking agents in fabrication. Thus, developing a simplified, one-step method to prepare PDA-based hydrogels without cross-linkers or oxidizers under mild conditions remains a key challenge.
Future research will focus on refining the design and synthesis of PDA-based nanocomposite hydrogels to improve drug-loading efficiency, controlled release, and long-term stability. Collaboration with medical device companies will be crucial to expedite the registration and commercialization of PDA-based products, ultimately advancing these hydrogels into more effective and practical clinical drug delivery tools.

Author Contributions

Conceptualization, F.T.; writing—original draft preparation, X.L., J.T., W.G., X.D. and K.C.; writing—review and editing, F.T. and X.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Project of Guizhou Provincial Science and Technology Program (Key 055 of Qiankehe-ZK [2023]); the Science and Technology Fund of Guizhou Provincial Health Commission (gzwkj2023-235); the Project of Special Funds for Science and Technology Cooperation in Guizhou Province and Zunyi City (Shengshikehe [2015] 53) and the National Natural Science Foundation of China (No. 32160225, 31460246).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Not applicable.

Acknowledgments

The authors sincerely appreciate the financial support provided by the aforementioned funding sources. We would like to extend our gratitude to Qiang Huang for his meticulous work in creating Figure 1. Additionally, we thank Figdraw (www.figdraw.com) for assistance with the creation of Figure 2 and Figure 3.

Conflicts of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

References

  1. Fan, S.; Sun, X.; Su, C.; Xue, Y.; Song, X.; Deng, R. Macrophages—Bone marrow mesenchymal stem cells crosstalk in bone healing. Front. Cell Dev. Biol. 2023, 11, 1193765. [Google Scholar] [CrossRef] [PubMed]
  2. Goodman, S.B.; Lin, T. Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches. Front. Bioeng. Biotechnol. 2020, 8, 641. [Google Scholar] [CrossRef] [PubMed]
  3. Habibovic, P. Strategic Directions in Osteoinduction and Biomimetics. Tissue Eng. Part A 2017, 23, 1295–1296. [Google Scholar] [CrossRef]
  4. Amini, A.R.; Laurencin, C.T.; Nukavarapu, S.P. Bone Tissue Engineering: Recent Advances and Challenges. Crit. Rev. Biomed. Eng. 2012, 40, 363–408. [Google Scholar] [CrossRef] [PubMed]
  5. Kawecki, F.; Clafshenkel, W.P.; Fortin, M.; Auger, F.A.; Fradette, J. Biomimetic Tissue-Engineered Bone Substitutes for Maxillofacial and Craniofacial Repair: The Potential of Cell Sheet Technologies. Adv. Healthc. Mater. 2018, 7, e1700919. [Google Scholar] [CrossRef]
  6. Subbiah, R.; Lin, E.Y.; Athirasala, A.; Romanowicz, G.E.; Lin, A.S.P.; Califano, J.V.; Guldberg, R.E.; Bertassoni, L.E. Engineering of an osteoinductive and growth factor-free injectable bone-like microgel for bone regeneration. Adv. Healthc. Mater. 2023, 12, e2200976. [Google Scholar] [CrossRef]
  7. Zeng, Y.; Hoque, J.; Varghese, S. Biomaterial-assisted local and systemic delivery of bioactive agents for bone repair. Acta Biomater. 2019, 93, 152–168. [Google Scholar] [CrossRef]
  8. Chen, J.; Ashames, A.; Buabeid, M.A.; Fahelelbom, K.M.; Ijaz, M.; Murtaza, G. Nanocomposites drug delivery systems for the healing of bone fractures. Int. J. Pharm. 2020, 585, 119477. [Google Scholar] [CrossRef]
  9. Wang, Y.; Newman, M.R.; Benoit, D.S. Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review. Eur. J. Pharm. Biopharm. 2018, 127, 223–236. [Google Scholar] [CrossRef]
  10. Bai, X.; Gao, M.; Syed, S.; Zhuang, J.; Xu, X.; Zhang, X.-Q. Bioactive hydrogels for bone regeneration. Bioact. Mater. 2018, 3, 401–417. [Google Scholar] [CrossRef]
  11. Shi, W.; Jiang, Y.; Wu, T.; Zhang, Y.; Li, T. Advancements in drug-loaded hydrogel systems for bone defect repair. Regen. Ther. 2023, 25, 174–185. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, H.; Wu, S.; Chen, W.; Hu, Y.; Geng, Z.; Su, J. Bone/cartilage targeted hydrogel: Strategies and applications. Bioact. Mater. 2022, 23, 156–169. [Google Scholar] [CrossRef] [PubMed]
  13. Wei, W.; Tang, J.; Hu, L.; Feng, Y.; Li, H.; Yin, C.; Tang, F. Experimental anti-tumor effect of emodin in suspension—In situ hydrogels formed with self-assembling peptide. Drug Deliv. 2021, 28, 1810–1821. [Google Scholar] [CrossRef] [PubMed]
  14. Raeisi, A.; Farjadian, F. Commercial hydrogel product for drug delivery based on route of administration. Front. Chem. 2024, 12, 1336717. [Google Scholar] [CrossRef]
  15. Farjadian, F.; Mirkiani, S.; Ghasemiyeh, P.; Kafshboran, H.R.; Mehdi-Alamdarlou, S.; Raeisi, A.; Esfandiarinejad, R.; Soleymani, S.; Goshtasbi, G.; Firouzabadi, N.; et al. Smart nanogels as promising platform for delivery of drug, gene, and vaccine; therapeutic applications and active targeting mechanism. Eur. Polym. J. 2024, 219, 113400. [Google Scholar] [CrossRef]
  16. Dhand, A.P.; Galarraga, J.H.; Burdick, J.A. Enhancing Biopolymer Hydrogel Functionality through Interpenetrating Networks. Trends Biotechnol. 2021, 39, 519–538. [Google Scholar] [CrossRef]
  17. Zheng, F.; Yang, X.; Li, J.; Tian, Z.; Xiao, B.; Yi, S.; Duan, L. Coordination with zirconium: A facile approach to improve the mechanical properties and thermostability of gelatin hydrogel. Int. J. Biol. Macromol. 2022, 205, 595–603. [Google Scholar] [CrossRef]
  18. Chen, M.; Le, D.Q.; Baatrup, A.; Nygaard, J.V.; Hein, S.; Bjerre, L.; Kassem, M.; Zou, X.; Bünger, C. Self-assembled composite matrix in a hierarchical 3-D scaffold for bone tissue engineering. Acta Biomater. 2011, 7, 2244–2255. [Google Scholar] [CrossRef]
  19. Wu, L.; Chen, G.; Li, Z. Layered Rare-Earth Hydroxide/Polyacrylamide Nanocomposite Hydrogels with Highly Tunable Photoluminescence. Small 2017, 13, 1604070. [Google Scholar] [CrossRef]
  20. Bedhiafi, T.; Idoudi, S.; Alhams, A.A.; Fernandes, Q.; Iqbal, H.; Basineni, R.; Uddin, S.; Dermime, S.; Merhi, M.; Billa, N. Applications of polydopaminic nanomaterials in mucosal drug delivery. J. Control. Release 2023, 353, 842–849. [Google Scholar] [CrossRef]
  21. Hong, S.; Na, Y.S.; Choi, S.; Song, I.T.; Kim, W.Y.; Lee, H. Non-Covalent Self-Assembly and Covalent Polymerization Co-Contribute to Polydopamine Formation. Adv. Funct. Mater. 2012, 22, 4711–4717. [Google Scholar] [CrossRef]
  22. Sarkari, S.; Khajehmohammadi, M.; Davari, N.; Li, D.; Yu, B. The effects of process parameters on polydopamine coatings employed in tissue engineering applications. Front. Bioeng. Biotechnol. 2022, 10, 1005413. [Google Scholar] [CrossRef]
  23. Hong, D.; Lee, H.; Kim, B.J.; Park, T.; Choi, J.Y.; Park, M.; Lee, J.; Cho, H.; Hong, S.-P.; Yang, S.H.; et al. A degradable polydopamine coating based on disulfide-exchange reaction. Nanoscale 2015, 7, 20149–20154. [Google Scholar] [CrossRef] [PubMed]
  24. Wang, Z.; Li, C.; Xu, J.; Wang, K.; Lu, X.; Zhang, H.; Qu, S.; Zhen, G.; Ren, F. Bioadhesive Microporous Architectures by Self-Assembling Polydopamine Microcapsules for Biomedical Applications. Chem. Mater. 2015, 27, 848–856. [Google Scholar] [CrossRef]
  25. Ku, S.H.; Ryu, J.; Hong, S.K.; Lee, H.; Park, C.B. General functionalization route for cell adhesion on non-wetting surfaces. Biomaterials 2010, 31, 2535–2541. [Google Scholar] [CrossRef] [PubMed]
  26. Su, T.; Zhang, M.; Zeng, Q.; Pan, W.; Huang, Y.; Qian, Y.; Dong, W.; Qi, X.; Shen, J. Mussel-inspired agarose hydrogel scaffolds for skin tissue engineering. Bioact. Mater. 2021, 6, 579–588. [Google Scholar] [CrossRef]
  27. Li, Y.; Liu, C.; Cheng, X.; Wang, J.; Pan, Y.; Zhang, S.; Jian, X. PDA-BPs integrated mussel-inspired multifunctional hydrogel coating on PPENK implants for anti-tumor therapy, antibacterial infection and bone regeneration. Bioact. Mater. 2023, 27, 546–559. [Google Scholar] [CrossRef]
  28. Li, Z.; Lin, H.; Shi, S.; Su, K.; Zheng, G.; Gao, S.; Zeng, X.; Ning, H.; Yu, M.; Li, X.; et al. Controlled and Sequential Delivery of Stromal Derived Factor-1 α (SDF-1α) and Magnesium Ions from Bifunctional Hydrogel for Bone Regeneration. Polymers 2022, 14, 2872. [Google Scholar] [CrossRef]
  29. Hathout, R.M.; Metwally, A.A.; El-Ahmady, S.H.; Metwally, E.S.; Ghonim, N.A.; Bayoumy, S.A.; Erfan, T.; Ashraf, R.; Fadel, M.; El-Kholy, A.I.; et al. Dual stimuli-responsive polypyrrole nanoparticles for anticancer therapy. J. Drug Deliv. Sci. Technol. 2018, 47, 176–180. [Google Scholar] [CrossRef]
  30. Ni, X.; Gao, Y.; Zhang, X.; Lei, Y.; Sun, G.; You, B. An eco-friendly smart self-healing coating with NIR and pH dual-responsive superhydrophobic properties based on biomimetic stimuli-responsive mesoporous polydopamine microspheres. Chem. Eng. J. 2021, 406, 126725. [Google Scholar] [CrossRef]
  31. Zhong, Z.; Fang, C.; He, S.; Zhang, T.; Liu, S.; Zhang, Y.; Wang, Q.; Ding, X.; Zhou, W.; Wang, X. Sequential Release Platform of Heparin and Urokinase with Dual Physical (NIR-II and Bubbles) Assistance for Deep Venous Thrombosis. ACS Biomater. Sci. Eng. 2020, 6, 6790–6799. [Google Scholar] [CrossRef]
  32. Li, H.; Li, Y.; Wang, X.; Hou, Y.; Hong, X.; Gong, T.; Zhang, Z.; Sun, X. Rational design of Polymeric Hybrid Micelles to Overcome Lymphatic and Intracellular Delivery Barriers in Cancer Immunotherapy. Theranostics 2017, 7, 4383–4398. [Google Scholar] [CrossRef]
  33. Xie, Y.; Zheng, Y.; Fan, J.; Wang, Y.; Yue, L.; Zhang, N. Novel Electronic–Ionic Hybrid Conductive Composites for Multifunctional Flexible Bioelectrode Based on in Situ Synthesis of Poly(dopamine) on Bacterial Cellulose. ACS Appl. Mater. Interfaces 2018, 10, 22692–22702. [Google Scholar] [CrossRef]
  34. Wang, L.; Han, L.; Xue, P.; Hu, X.; Wong, S.-W.; Deng, M.; Tseng, H.C.; Huang, B.-W.; Ko, C.-C. Dopamine suppresses osteoclast differentiation via cAMP/PKA/CREB pathway. Cell. Signal. 2021, 78, 109847. [Google Scholar] [CrossRef] [PubMed]
  35. Yuan, Z.; Tao, B.; He, Y.; Mu, C.; Liu, G.; Zhang, J.; Liao, Q.; Liu, P.; Cai, K. Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy. Biomaterials 2019, 223, 119479. [Google Scholar] [CrossRef] [PubMed]
  36. Sheng, W.; Li, W.; Yu, B.; Li, B.; Jordan, R.; Jia, X.; Zhou, F. Mussel-Inspired Two-Dimensional Freestanding Alkyl-Polydopamine Janus Nanosheets. Angew. Chem. Int. Ed. Engl. 2019, 58, 12018–12022. [Google Scholar] [CrossRef] [PubMed]
  37. Park, J.; Brust, T.F.; Lee, H.J.; Lee, S.C.; Watts, V.J.; Yeo, Y. Polydopamine-Based Simple and Versatile Surface Modification of Polymeric Nano Drug Carriers. ACS Nano 2014, 8, 3347–3356. [Google Scholar] [CrossRef]
  38. Zhu, M.; Shi, Y.; Shan, Y.; Guo, J.; Song, X.; Wu, Y.; Wu, M.; Lu, Y.; Chen, W.; Xu, X.; et al. Recent developments in mesoporous polydopamine-derived nanoplatforms for cancer theranostics. J. Nanobiotechnol. 2021, 19, 387. [Google Scholar] [CrossRef]
  39. Jing, X.; Mi, H.-Y.; Lin, Y.-J.; Enriquez, E.; Peng, X.-F.; Turng, L.-S. Highly Stretchable and Biocompatible Strain Sensors Based on Mussel-Inspired Super-Adhesive Self-Healing Hydrogels for Human Motion Monitoring. ACS Appl. Mater. Interfaces 2018, 10, 20897–20909. [Google Scholar] [CrossRef]
  40. Rossi, F.; Kurashina, Y.; Onoe, H. Can nanoparticles enhance drug-delivery performance of hydrogels? Nanomedicine 2023, 18, 653–657. [Google Scholar] [CrossRef]
  41. Mohammadpour, R.; Dobrovolskaia, M.A.; Cheney, D.L.; Greish, K.F.; Ghandehari, H. Subchronic and chronic toxicity evaluation of inorganic nanoparticles for delivery applications. Adv. Drug Deliv. Rev. 2019, 144, 112–132. [Google Scholar] [CrossRef] [PubMed]
  42. Paris, J.L.; Baeza, A.; Vallet-Regí, M. Overcoming the stability, toxicity, and biodegradation challenges of tumor stimuli-responsive inorganic nanoparticles for delivery of cancer therapeutics. Expert Opin. Drug Deliv. 2019, 16, 1095–1112. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, X.; Yu, X.; Wang, X.; Qi, M.; Pan, J.; Wang, Q. One-Step Nanosurface Self-Assembly of d-Peptides Renders Bubble-Free Ultrasound Theranostics. Nano Lett. 2019, 19, 2251–2258. [Google Scholar] [CrossRef]
  44. Zhu, J.; Feng, C.; Zhang, W.; Zhong, M.; Tang, W.; Wang, Z.; Shi, H.; Yin, Z.; Shi, J.; Huang, Y.; et al. Activation of dopamine receptor D1 promotes osteogenic differentiation and reduces glucocorticoid-induced bone loss by upregulating the ERK1/2 signaling pathway. Mol. Med. 2022, 28, 23. [Google Scholar] [CrossRef] [PubMed]
  45. Zhu, Y.; Liu, D.; Wang, X.; He, Y.; Luan, W.; Qi, F.; Ding, J. Polydopamine-mediated covalent functionalization of collagen on a titanium alloy to promote biocompatibility with soft tissues. J. Mater. Chem. B 2019, 7, 2019–2031. [Google Scholar] [CrossRef]
  46. Kim, H.; Lee, Y.H.; Kim, N.K.; Kang, I.K. Immobilization of Collagen on the Surface of a PEEK Implant with Monolayer Nanopores. Polymers 2022, 14, 1633. [Google Scholar] [CrossRef]
  47. Xue, X.; Hu, Y.; Wang, S.; Chen, X.; Jiang, Y.; Su, J. Fabrication of physical and chemical crosslinked hydrogels for bone tissue engineering. Bioact. Mater. 2021, 12, 327–339. [Google Scholar] [CrossRef]
  48. Lu, G.; Xu, Y.; Liu, Q.; Chen, M.; Sun, H.; Wang, P.; Wang, Y.; Li, X.; Hui, X.; Luo, E.; et al. An instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis. Nat. Commun. 2022, 13, 2499. [Google Scholar] [CrossRef]
  49. Wang, Y.; Qi, H.; Miron, R.J.; Zhang, Y. Modulating macrophage polarization on titanium implant surface by poly(dopamine)-assisted immobilization of IL4. Clin. Implant. Dent. Relat. Res. 2019, 21, 977–986. [Google Scholar] [CrossRef]
  50. Su, J.; Du, Z.; Xiao, L.; Wei, F.; Yang, Y.; Li, M.; Qiu, Y.; Liu, J.; Chen, J.; Xiao, Y. Graphene oxide coated Titanium Surfaces with Osteoimmunomodulatory Role to Enhance Osteogenesis. Mater. Sci. Eng. C 2020, 113, 110983. [Google Scholar] [CrossRef]
  51. Zhang, D.; Zheng, H.; Geng, K.; Shen, J.; Feng, X.; Xu, P.; Duan, Y.; Li, Y.; Wu, R.; Gou, Z.; et al. Large fuzzy biodegradable polyester microspheres with dopamine deposition enhance cell adhesion and bone regeneration in vivo. Biomaterials 2021, 272, 120783. [Google Scholar] [CrossRef] [PubMed]
  52. Agilan, P.; Saranya, K.; Rajendran, N. Bio-inspired polydopamine incorporated titania nanotube arrays for biomedical applications. Colloids Surf. A Physicochem. Eng. Asp. 2021, 629, 127489. [Google Scholar] [CrossRef]
  53. Qiaoxia, L.; Yujie, Z.; Meng, Y.; Yizhu, C.; Yan, W.; Yinchun, H.; Xiaojie, L.; Weiyi, C.; Di, H. Hydroxyapatite/tannic acid composite coating formation based on Ti modified by TiO2 nanotubes. Colloids Surf. B Biointerfaces 2020, 196, 111304. [Google Scholar] [CrossRef] [PubMed]
  54. Yang, H.; Xu, Y.; Zhu, M.; Gu, Y.; Zhang, W.; Shao, H.; Wang, Y.; Ping, Z.; Hu, X.; Wang, L.; et al. Inhibition of titanium-particle-induced inflammatory osteolysis after local administration of dopamine and suppression of osteoclastogenesis via D2-like receptor signaling pathway. Biomaterials 2016, 80, 1–10. [Google Scholar] [CrossRef]
  55. Li, Y.; Yang, C.; Yin, X.; Sun, Y.; Weng, J.; Zhou, J.; Feng, B. Inflammatory responses to micro/nano-structured titanium surfaces with silver nanoparticles in vitro. J. Mater. Chem. B 2019, 7, 3546–3559. [Google Scholar] [CrossRef]
  56. Feng, P.; Liu, M.; Peng, S.; Bin, S.; Zhao, Z.; Shuai, C. Polydopamine modified polycaprolactone powder for fabrication bone scaffold owing intrinsic bioactivity. J. Mater. Res. Technol. 2021, 15, 3375–3385. [Google Scholar] [CrossRef]
  57. Cheng, J.; Liu, H.; Zhao, B.; Shen, R.; Liu, D.; Hong, J.; Wei, H.; Xi, P.; Chen, F.; Bai, D. MC3T3-E1 preosteoblast cell-mediated mineralization of hydroxyapatite by poly-dopamine-functionalized graphene oxide. J. Bioact. Compat. Polym. 2015, 30, 289–301. [Google Scholar] [CrossRef]
  58. Chen, J.; Mei, M.L.; Li, Q.-L.; Chu, C.-H. Mussel-inspired silver-nanoparticle coating on porous titanium surfaces to promote mineralization. RSC Adv. 2016, 6, 104025–104035. [Google Scholar] [CrossRef]
  59. Wu, M.; Wang, T.; Wang, Y.; Wang, H. Ultrafast bone-like apatite formation on bioactive tricalcium silicate cement using mussel-inspired polydopamine. Ceram. Int. 2019, 45, 3033–3043. [Google Scholar] [CrossRef]
  60. Lin, H.; Fu, Y.; Gao, Y.; Mo, A. Integrated design of a mussel-inspired hydrogel biofilm composite structure to guide bone regeneration. Macromol. Mater. Eng. 2020, 305, 2000064. [Google Scholar] [CrossRef]
  61. Chien, C.; Liu, T.; Kuo, W.; Wang, M.; Tsai, W. Dopamine-assisted immobilization of hydroxyapatite nanoparticles and RGD peptides to improve the osteoconductivity of titanium. J. Biomed. Mater. Res. Part A 2013, 101, 740–747. [Google Scholar] [CrossRef] [PubMed]
  62. Bachir, A.I.; Zareno, J.; Moissoglu, K.; Plow, E.F.; Gratton, E.; Horwitz, A.R. Integrin-associated complexes form hierarchically with variable stoichiometry in nascent adhesions. Curr. Biol. 2014, 24, 1845–1853. [Google Scholar] [CrossRef]
  63. Yuan, Z.; Huang, S.; Lan, S.; Xiong, H.; Tao, B.; Ding, Y.; Liu, Y.; Liu, P.; Cai, K. Surface engineering of titanium implants with enzyme-triggered antibacterial properties and enhanced osseointegration in vivo. J. Mater. Chem. B 2018, 6, 8090–8104. [Google Scholar] [CrossRef] [PubMed]
  64. Yin, H.-M.; Mao, C.; Liu, W.; Liu, Y.-H.; Ren, Y.; Xu, L.; Xu, J.-Z.; Zhao, B.; Gul, R.M.; Li, Z.-M. Nanotopographical polymeric surface with mussel-inspired decoration to enhance osteoblast differentiation. Appl. Surf. Sci. 2019, 481, 987–993. [Google Scholar] [CrossRef]
  65. Yang, Y.; Xu, T.; Bei, H.P.; Zhao, Y.; Zhao, X. Sculpting bio-inspired surface textures: An adhesive janus periosteum. Adv. Funct. Mater. 2021, 31, 2104636. [Google Scholar] [CrossRef]
  66. Hanami, K.; Nakano, K.; Saito, K.; Okada, Y.; Yamaoka, K.; Kubo, S.; Kondo, M.; Tanaka, Y. Dopamine D2-like receptor signaling suppresses human osteoclastogenesis. Bone 2013, 56, 1–8. [Google Scholar] [CrossRef]
  67. Chiang, T.-I.; Lane, H.-Y.; Lin, C.-H. D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density. Sci. Rep. 2020, 10, 13236. [Google Scholar] [CrossRef]
  68. Liu, Y.; Chen, Q.; Jeong, H.-W.; Han, D.; Fabian, J.; Drexler, H.C.; Stehling, M.; Schöler, H.R.; Adams, R.H. Dopamine signaling regulates hematopoietic stem and progenitor cell function. Blood 2021, 138, 2051–2065. [Google Scholar] [CrossRef]
  69. Wang, C.-X.; Ge, X.-Y.; Wang, M.-Y.; Ma, T.; Zhang, Y.; Lin, Y. Dopamine D1 receptor-mediated activation of the ERK signaling pathway is involved in the osteogenic differentiation of bone mesenchymal stem cells. Stem Cell Res. Ther. 2020, 11, 12. [Google Scholar] [CrossRef]
  70. Taylor, E.L.; Weaver, S.R.; Lorang, I.M.; Arnold, K.M.; Bradley, E.W.; de Velasco, E.M.F.; Wickman, K.; Westendorf, J.J. GIRK3 deletion facilitates kappa opioid signaling in chondrocytes, delays vascularization and promotes bone lengthening in mice. Bone 2022, 159, 116391. [Google Scholar] [CrossRef]
  71. Wang, J.; Cui, Y.; Zhang, B.; Sun, S.; Xu, H.; Yao, M.; Wu, D.; Wang, Y. Polydopamine-Modified functional materials promote bone regeneration. Mater. Des. 2024, 238, 112655. [Google Scholar] [CrossRef]
  72. Gao, B.; Chen, L.; Zhao, Y.; Yan, X.; Wang, X.; Zhou, C.; Shi, Y.; Xue, W. Methods to prepare dopamine/polydopamine modified alginate hydrogels and their special improved properties for drug delivery. Eur. Polym. J. 2019, 110, 192–201. [Google Scholar] [CrossRef]
  73. Jing, X.; Mi, H.-Y.; Napiwocki, B.N.; Peng, X.-F.; Turng, L.-S. Mussel-inspired electroactive chitosan/graphene oxide composite hydrogel with rapid self-healing and recovery behavior for tissue engineering. Carbon 2017, 125, 557–570. [Google Scholar] [CrossRef]
  74. Di, X.; Hang, C.; Xu, Y.; Ma, Q.; Li, F.; Sun, P.; Wu, G. Bioinspired tough, conductive hydrogels with thermally reversible adhesiveness based on nanoclay confined NIPAM polymerization and a dopamine modified polypeptide. Mater. Chem. Front. 2020, 4, 189–196. [Google Scholar] [CrossRef]
  75. Wang, X.; Wang, C.; Wang, X.; Wang, Y.; Zhang, Q.; Cheng, Y. A Polydopamine Nanoparticle-Knotted Poly(ethylene glycol) Hydrogel for On-Demand Drug Delivery and Chemo-photothermal Therapy. Chem. Mater. 2017, 29, 1370–1376. [Google Scholar] [CrossRef]
  76. Han, L.; Li, P.; Tang, P.; Wang, X.; Zhou, T.; Wang, K.; Ren, F.; Guo, T.; Lu, X. Mussel-inspired cryogels for promoting wound regeneration through photobiostimulation, modulating inflammatory responses and suppressing bacterial invasion. Nanoscale 2019, 11, 15846–15861. [Google Scholar] [CrossRef]
  77. Liu, Y.; Xi, Y.; Zhao, J.; Zhao, J.; Li, J.; Huang, G.; Li, J.; Fang, F.; Gu, L.; Wang, S. Preparation of therapeutic-laden konjac hydrogel for tumor combination therapy. Chem. Eng. J. 2019, 375, 122048. [Google Scholar] [CrossRef]
  78. Zeng, J.; Shi, D.; Gu, Y.; Kaneko, T.; Zhang, L.; Zhang, H.; Kaneko, D.; Chen, M. Injectable and Near-Infrared-Responsive Hydrogels Encapsulating Dopamine-Stabilized Gold Nanorods with Long Photothermal Activity Controlled for Tumor Therapy. Biomacromolecules 2019, 20, 3375–3384. [Google Scholar] [CrossRef]
  79. Wu, Y.; Wang, H.; Gao, F.; Xu, Z.; Dai, F.; Liu, W. An Injectable Supramolecular Polymer Nanocomposite Hydrogel for Prevention of Breast Cancer Recurrence with Theranostic and Mammoplastic Functions. Adv. Funct. Mater. 2018, 28, 1801000. [Google Scholar] [CrossRef]
  80. Song, J.; Hu, H.; Jian, C.; Wu, K.; Chen, X. New Generation of Gold Nanoshell-Coated Esophageal Stent: Preparation and Biomedical Applications. ACS Appl. Mater. Interfaces 2016, 8, 27523–27529. [Google Scholar] [CrossRef]
  81. Han, L.; Liu, K.; Wang, M.; Wang, K.; Fang, L.; Chen, H.; Zhou, J.; Lu, X. Mussel-Inspired Adhesive and Conductive Hydrogel with Long-Lasting Moisture and Extreme Temperature Tolerance. Adv. Funct. Mater. 2018, 28, 1704195. [Google Scholar] [CrossRef]
  82. Wan, Z.; Dong, Q.; Guo, X.; Bai, X.; Zhang, X.; Zhang, P.; Liu, Y.; Lv, L.; Zhou, Y. A dual-responsive polydopamine-modified hydroxybutyl chitosan hydrogel for sequential regulation of bone regeneration. Carbohydr. Polym. 2022, 297, 120027. [Google Scholar] [CrossRef]
  83. Zhang, S.; Xu, K.; Darabi, M.A.; Yuan, Q.; Xing, M. Mussel-inspired alginate gel promoting the osteogenic differentiation of mesenchymal stem cells and anti-infection. Mater. Sci. Eng. C 2016, 69, 496–504. [Google Scholar] [CrossRef]
  84. Chen, S.; Wang, Y.; Zhang, X.; Ma, J.; Wang, M. Double-crosslinked bifunctional hydrogels with encapsulated anti-cancer drug for bone tumor cell ablation and bone tissue regeneration. Colloids Surf. B Biointerfaces 2022, 213, 112364. [Google Scholar] [CrossRef]
  85. Gan, D.; Wang, Z.; Xie, C.; Wang, X.; Xing, W.; Ge, X.; Yuan, H.; Wang, K.; Tan, H.; Lu, X. Mussel-Inspired Tough Hydrogel with In Situ Nanohydroxyapatite Mineralization for Osteochondral Defect Repair. Adv. Healthc. Mater. 2019, 12, e2203040. [Google Scholar] [CrossRef] [PubMed]
  86. Wu, Y.; Zhang, X.; Tan, B.; Shan, Y.; Zhao, X.; Liao, J. Near-infrared light control of GelMA/PMMA/PDA hydrogel with mild photothermal therapy for skull regeneration. Mater. Sci. Eng. C Mater. Biol. Appl. 2022, 133, 112641. [Google Scholar] [CrossRef] [PubMed]
  87. Dashtimoghadam, E.; Fahimipour, F.; Tongas, N.; Tayebi, L. Microfluidic fabrication of microcarriers with sequential delivery of VEGF and BMP-2 for bone regeneration. Sci. Rep. 2020, 10, 11764. [Google Scholar] [CrossRef]
  88. Li, X.; Pang, Y.; Guan, L.; Li, L.; Zhu, Y.; Whittaker, A.K.; Yang, B.; Zhu, S.; Lin, Q. Mussel-inspired antimicrobial hydrogel with cellulose nanocrystals/tannic acid modified silver nanoparticles for enhanced calvarial bone regeneration. Int. J. Biol. Macromol. 2024, 270 Pt 2, 132419. [Google Scholar] [CrossRef]
  89. Han, Z.; Wang, F.; Xiong, W.; Meng, C.; Yao, Y.; Cui, W.; Zhang, M. Precise Cell Type Electrical Stimulation Therapy Via Force-electric Hydrogel Microspheres for Cartilage Healing. Adv. Mater. 2024, 37, e2414555. [Google Scholar] [CrossRef]
  90. Sun, H.; Shang, Y.; Guo, J.; Maihemuti, A.; Shen, S.; Shi, Y.; Liu, H.; Che, J.; Jiang, Q. Artificial Periosteum with Oriented Surface Nanotopography and High Tissue Adherent Property. ACS Appl. Mater. Interfaces 2023, 15, 45549–45560. [Google Scholar] [CrossRef]
  91. Chen, S.; Tan, S.; Zheng, L.; Wang, M. Multilayered Shape-Morphing Scaffolds with a Hierarchical Structure for Uterine Tissue Regeneration. ACS Appl. Mater. Interfaces 2024, 16, 6772–6788. [Google Scholar] [CrossRef]
  92. Li, H.; Zhao, T.; Yuan, Z.; Gao, T.; Yang, Y.; Li, R.; Tian, Q.; Tang, P.; Guo, Q.; Zhang, L. Cartilage lacuna-biomimetic hydrogel microspheres endowed with integrated biological signal boost endogenous articular cartilage regeneration. Bioact. Mater. 2024, 41, 61–82. [Google Scholar] [CrossRef]
  93. Wu, M.; Liu, H.; Li, D.; Zhu, Y.; Wu, P.; Chen, Z.; Chen, F.; Chen, Y.; Deng, Z.; Cai, L. Smart-Responsive Multifunctional Therapeutic System for Improved Regenerative Microenvironment and Accelerated Bone Regeneration via Mild Photothermal Therapy. Adv. Sci. 2024, 11, e2304641. [Google Scholar] [CrossRef] [PubMed]
  94. Wu, M.; Zhang, Y.; Zhao, Y.; Chu, L.; Meng, X.; Ye, L.; Li, X.; Wang, Z.; Wu, P. Photoactivated Hydrogel Therapeutic System with MXene-Based Nanoarchitectonics Potentiates Endogenous Bone Repair Through Reshaping the Osteo-Vascularization Network. Small 2024, 20, e2403003. [Google Scholar] [CrossRef] [PubMed]
  95. Kang, J.; Li, Y.; Qin, Y.; Huang, Z.; Wu, Y.; Sun, L.; Wang, C.; Wang, W.; Feng, G.; Qi, Y. In Situ Deposition of Drug and Gene Nanoparticles on a Patterned Supramolecular Hydrogel to Construct a Directionally Osteochondral Plug. Nano-Micro Lett. 2023, 16, 18. [Google Scholar] [CrossRef] [PubMed]
  96. Zhang, R.; Jo, J.-I.; Kanda, R.; Nishiura, A.; Hashimoto, Y.; Matsumoto, N. Bioactive Polyetheretherketone with Gelatin Hydrogel Leads to Sustained Release of Bone Morphogenetic Protein-2 and Promotes Osteogenic Differentiation. Int. J. Mol. Sci. 2023, 24, 12741. [Google Scholar] [CrossRef]
  97. Li, M.; Wu, H.; Gao, K.; Wang, Y.; Hu, J.; Guo, Z.; Hu, R.; Zhang, M.; Pang, X.; Guo, M.; et al. Smart Implantable Hydrogel for Large Segmental Bone Regeneration. Adv. Healthc. Mater. 2024, 13, e2402916. [Google Scholar] [CrossRef]
  98. Wu, M.; Chen, F.; Liu, H.; Wu, P.; Yang, Z.; Zhang, Z.; Su, J.; Cai, L.; Zhang, Y. Bioinspired sandwich-like hybrid surface functionalized scaffold capable of regulating osteogenesis, angiogenesis, and osteoclastogenesis for robust bone regeneration. Mater. Today Bio 2022, 17, 100458. [Google Scholar] [CrossRef]
  99. Wu, Y.; Li, X.; Sun, Y.; Tan, X.; Wang, C.; Wang, Z.; Ye, L. Multiscale design of stiffening and ROS scavenging hydrogels for the augmentation of mandibular bone regeneration. Bioact. Mater. 2022, 20, 111–125. [Google Scholar] [CrossRef]
  100. Wu, M.; Liu, H.; Zhu, Y.; Wu, P.; Chen, Y.; Deng, Z.; Zhu, X.; Cai, L. Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis. Theranostics 2024, 14, 4014–4057. [Google Scholar] [CrossRef]
  101. Shi, W.; Gao, Y.; Wu, Y.; Sun, J.; Xu, B.; Lu, X.; Wang, Q. A multifunctional polydopamine/genipin/alendronate nanoparticle licences fibrin hydrogels osteoinductive and immunomodulatory potencies for repairing bone defects. Int. J. Biol. Macromol. 2023, 249, 126072. [Google Scholar] [CrossRef] [PubMed]
  102. Ma, K.; Yang, L.; Li, W.; Chen, K.; Shang, L.; Bai, Y.; Zhao, Y. Mussel-inspired multi-bioactive microsphere scaffolds for bone defect photothermal therapy. Mater. Today Bio 2024, 29, 101363. [Google Scholar] [CrossRef]
  103. Wu, M.; Liu, H.; Zhu, Y.; Chen, F.; Chen, Z.; Guo, L.; Wu, P.; Li, G.; Zhang, C.; Wei, R.; et al. Mild Photothermal-Stimulation Based on Injectable and Photocurable Hydrogels Orchestrates Immunomodulation and Osteogenesis for High-Performance Bone Regeneration. Small 2023, 19, e2300111. [Google Scholar] [CrossRef]
  104. Huang, L.; Wu, T.; Sun, J.; Lin, X.; Peng, Y.; Zhang, R.; Gao, Y.; Xu, S.; Sun, Y.; Zhou, Y.; et al. Biocompatible chitin-based Janus hydrogel membranes for periodontal repair. Acta Biomater. 2024, 190, 219–232. [Google Scholar] [CrossRef] [PubMed]
  105. Xu, H.; Zhang, G.; Xu, K.; Wang, L.; Yu, L.; Xing, M.M.; Qiu, X. Mussel-inspired dual-functional PEG hydrogel inducing mineralization and inhibiting infection in maxillary bone reconstruction. Mater. Sci. Eng. C 2018, 90, 379–386. [Google Scholar] [CrossRef] [PubMed]
  106. Wu, P.; Shen, L.; Liu, H.-F.; Zou, X.-H.; Zhao, J.; Huang, Y.; Zhu, Y.-F.; Li, Z.-Y.; Xu, C.; Luo, L.-H.; et al. The marriage of immunomodulatory, angiogenic, and osteogenic capabilities in a piezoelectric hydrogel tissue engineering scaffold for military medicine. Mil. Med. Res. 2023, 10, 35. [Google Scholar] [CrossRef]
  107. Chen, Y.-W.; Shen, Y.-F.; Ho, C.-C.; Yu, J.; Wu, Y.-H.A.; Wang, K.; Shih, C.-T.; Shie, M.-Y. Osteogenic and angiogenic potentials of the cell-laden hydrogel/mussel-inspired calcium silicate complex hierarchical porous scaffold fabricated by 3D bioprinting. Mater. Sci. Eng. C 2018, 91, 679–687. [Google Scholar] [CrossRef]
  108. Liu, C.; Wu, J.; Gan, D.; Li, Z.; Shen, J.; Tang, P.; Luo, S.; Li, P.; Lu, X.; Zheng, W. The characteristics of mussel-inspired nHA/OSA injectable hydrogel and repaired bone defect in rabbit. J. Biomed. Mater. Res. Part B Appl. Biomater. 2020, 108, 1814–1825. [Google Scholar] [CrossRef]
  109. Pang, Y.; Guan, L.; Zhu, Y.; Niu, R.; Zhu, S.; Lin, Q. Gallic acid-grafted chitosan antibacterial hydrogel incorporated with polydopamine-modified hydroxyapatite for enhancing bone healing. Front. Bioeng. Biotechnol. 2023, 11, 1162202. [Google Scholar] [CrossRef]
  110. Kwack, K.H.; Ji, J.Y.; Park, B.; Heo, J.S. Fucoidan (Undaria pinnatifida)/Polydopamine Composite-Modified Surface Promotes Osteogenic Potential of Periodontal Ligament Stem Cells. Mar. Drugs 2022, 20, 181. [Google Scholar] [CrossRef]
  111. Deng, H.; Shu, X.; Wang, Y.; Zhang, J.; Yin, Y.; Wu, F.; He, J. Matrix Stiffness Regulated Endoplasmic Reticulum Stress-mediated Apoptosis of Osteosarcoma Cell through Ras Signal Cascades. Cell Biochem. Biophys. 2023, 81, 839–850. [Google Scholar] [CrossRef] [PubMed]
  112. Zhong, W.; Xiong, Y.; Wang, X.; Yu, T.; Zhou, C. Synthesis and characterization of multifunctional organic-inorganic composite hydrogel formed with tissue-adhesive property and inhibiting infection. Mater. Sci. Eng. C 2021, 118, 111532. [Google Scholar] [CrossRef] [PubMed]
  113. Wu, Y.; Lyu, Z.; Hu, F.; Yang, L.; Yang, K.; Chen, M.; Wang, Y. A chondroitin sulphate hydrogel with sustained release of SDF-1α for extensive cartilage defect repair through induction of cell homing and promotion of chondrogenesis. J. Mater. Chem. B 2024, 12, 8672–8687. [Google Scholar] [CrossRef]
  114. Zhou, Q.; Liu, J.; Yan, J.; Guo, Z.; Zhang, F. Magnetic microspheres mimicking certain functions of macrophages: Towards precise antibacterial potency for bone defect healing. Mater. Today Bio 2023, 20, 100651. [Google Scholar] [CrossRef]
  115. Li, S.; Jia, C.; Han, H.; Yang, Y.; Xiaowen, Y.; Chen, Z. Characterization and biocompatibility of a bilayer PEEK-based scaffold for guiding bone regeneration. BMC Oral Health 2024, 24, 1138. [Google Scholar] [CrossRef]
  116. Liu, H.; Li, K.; Yi, D.; Ding, Y.; Gao, Y.; Zheng, X. Deferoxamine-Loaded Chitosan-Based Hydrogel on Bone Implants Showing Enhanced Bond Strength and Pro-Angiogenic Effects. J. Funct. Biomater. 2024, 15, 112. [Google Scholar] [CrossRef] [PubMed]
  117. Fang, X.; Wang, J.; Ye, C.; Lin, J.; Ran, J.; Jia, Z.; Gong, J.; Zhang, Y.; Xiang, J.; Lu, X.; et al. Polyphenol-mediated redox-active hydrogel with H2S gaseous-bioelectric coupling for periodontal bone healing in diabetes. Nat. Commun. 2024, 15, 9071. [Google Scholar] [CrossRef]
  118. Im, S.; Choe, G.; Seok, J.M.; Yeo, S.J.; Lee, J.H.; Kim, W.D.; Lee, J.Y.; Park, S.A. An osteogenic bioink composed of alginate, cellulose nanofibrils, and polydopamine nanoparticles for 3D bioprinting and bone tissue engineering. Int. J. Biol. Macromol. 2022, 205, 520–529. [Google Scholar] [CrossRef]
  119. Ma, W.; Yang, M.; Wu, C.; Wang, S.; Du, M. Bioinspired self-healing injectable nanocomposite hydrogels based on oxidized dextran and gelatin for growth-factor-free bone regeneration. Int. J. Biol. Macromol. 2023, 251, 126145. [Google Scholar] [CrossRef]
  120. Luo, S.; Wu, J.; Jia, Z.; Tang, P.; Sheng, J.; Xie, C.; Liu, C.; Gan, D.; Hu, D.; Zheng, W.; et al. An Injectable, Bifunctional Hydrogel with Photothermal Effects for Tumor Therapy and Bone Regeneration. Macromol. Biosci. 2019, 19, e1900047. [Google Scholar] [CrossRef]
  121. Jung, A.; Makkar, P.; Amirian, J.; Lee, B.-T. A novel hybrid multichannel biphasic calcium phosphate granule-based composite scaffold for cartilage tissue regeneration. J. Biomater. Appl. 2018, 32, 775–787. [Google Scholar] [CrossRef] [PubMed]
  122. Douglas, T.; Wlodarczyk, M.; Pamula, E.; Declercq, H.; de Mulder, E.; Bucko, M.; Balcaen, L.; Vanhaecke, F.; Cornelissen, R.; Dubruel, P.; et al. Enzymatic mineralization of gellan gum hydrogel for bone tissue-engineering applications and its enhancement by polydopamine. J. Tissue Eng. Regen. Med. 2014, 8, 906–918. [Google Scholar] [CrossRef]
  123. Liu, Y.; Wei, X.; Yang, T.; Wang, X.; Li, T.; Sun, M.; Jiao, K.; Jia, W.; Yang, Y.; Yan, Y.; et al. Hyaluronic acid methacrylate/Pluronic F127 hydrogel enhanced with spermidine-modified mesoporous polydopamine nanoparticles for efficient synergistic periodontitis treatment. Int. J. Biol. Macromol. 2024, 281 Pt 1, 136085. [Google Scholar] [CrossRef] [PubMed]
  124. Li, Y.; Tang, S.; Luo, Z.; Liu, K.; Luo, Y.; Wen, W.; Ding, S.; Li, L.; Liu, M.; Zhou, C.; et al. Chitin whisker/chitosan liquid crystal hydrogel assisted scaffolds with bone-like ECM microenvironment for bone regeneration. Carbohydr. Polym. 2024, 332, 121927. [Google Scholar] [CrossRef] [PubMed]
  125. Ma, W.; Chen, H.; Cheng, S.; Wu, C.; Wang, L.; Du, M. Gelatin hydrogel reinforced with mussel-inspired polydopamine-functionalized nanohydroxyapatite for bone regeneration. Int. J. Biol. Macromol. 2023, 240, 124287. [Google Scholar] [CrossRef]
  126. Li, M.; Wei, F.; Yin, X.; Xiao, L.; Yang, L.; Su, J.; Weng, J.; Feng, B.; Xiao, Y.; Zhou, Y. Synergistic regulation of osteoimmune microenvironment by IL-4 and RGD to accelerate osteogenesis. Mater. Sci. Eng. C 2020, 109, 110508. [Google Scholar] [CrossRef]
  127. Yan, L.; Zhou, T.; Ni, R.; Jia, Z.; Jiang, Y.; Guo, T.; Wang, K.; Chen, X.; Han, L.; Lu, X. Adhesive Gelatin-Catechol Complex Reinforced Poly(Acrylic Acid) Hydrogel with Enhanced Toughness and Cell Affinity for Cartilage Regeneration. ACS Appl. Bio Mater. 2020, 5, 4366–4377. [Google Scholar] [CrossRef]
  128. Zhang, F.-X.; Liu, P.; Ding, W.; Meng, Q.-B.; Su, D.-H.; Zhang, Q.-C.; Lian, R.-X.; Yu, B.-Q.; Zhao, M.-D.; Dong, J.; et al. Injectable Mussel-Inspired highly adhesive hydrogel with exosomes for endogenous cell recruitment and cartilage defect regeneration. Biomaterials 2021, 278, 121169. [Google Scholar] [CrossRef]
  129. Xu, Y.; Zhao, S.; Weng, Z.; Zhang, W.; Wan, X.; Cui, T.; Ye, J.; Liao, L.; Wang, X. Jelly-Inspired Injectable Guided Tissue Regeneration Strategy with Shape Auto-Matched and Dual-Light-Defined Antibacterial/Osteogenic Pattern Switch Properties. ACS Appl. Mater. Interfaces 2020, 12, 54497–54506. [Google Scholar] [CrossRef]
  130. Ren, S.; Tang, X.; Liu, L.; Meng, F.; Yang, X.; Li, N.; Zhang, Z.; Aimaijiang, M.; Liu, M.; Liu, X.; et al. Reinforced Blood-Derived Protein Hydrogels Enable Dual-Level Regulation of Bio-Physiochemical Microenvironments for Personalized Bone Regeneration with Remarkable Enhanced Efficacy. Nano Lett. 2022, 22, 3904–3913. [Google Scholar] [CrossRef]
  131. Li, Y.; Liu, X.; Li, B.; Zheng, Y.; Han, Y.; Chen, D.-F.; Yeung, K.W.K.; Cui, Z.; Liang, Y.; Li, Z.; et al. Near-Infrared Light Triggered Phototherapy and Immunotherapy for Elimination of Methicillin-Resistant Staphylococcus aureus Biofilm Infection on Bone Implant. ACS Nano 2020, 14, 8157–8170. [Google Scholar] [CrossRef] [PubMed]
  132. Li, N.; Liu, L.; Wei, C.; Ren, S.; Liu, X.; Wang, X.; Song, J.; Li, Y.; Wang, Z.; Qiao, S.; et al. Immunomodulatory Blood-Derived Hybrid Hydrogels as Multichannel Microenvironment Modulators for Augmented Bone Regeneration. ACS Appl. Mater. Interfaces 2022, 14, 53523–53534. [Google Scholar] [CrossRef]
  133. Yin, J.; Han, Q.; Zhang, J.; Liu, Y.; Gan, X.; Xie, K.; Xie, L.; Deng, Y. MXene-Based Hydrogels Endow Polyetheretherketone with Effective Osteogenicity and Combined Treatment of Osteosarcoma and Bacterial Infection. ACS Appl. Mater. Interfaces 2020, 12, 45891–45903. [Google Scholar] [CrossRef]
  134. Zheng, L.; Li, D.; Wang, W.; Zhang, Q.; Zhou, X.; Liu, D.; Zhang, J.; You, Z.; Zhang, J.; He, C. Bilayered Scaffold Prepared from a Kartogenin-Loaded Hydrogel and BMP-2-Derived Peptide-Loaded Porous Nanofibrous Scaffold for Osteochondral Defect Repair. ACS Biomater. Sci. Eng. 2019, 5, 4564–4573. [Google Scholar] [CrossRef]
  135. Abie, N.; Ünlü, C.; Pinho, A.R.; Gomes, M.C.; Remmler, T.; Herb, M.; Grumme, D.; Tabesh, E.; Shahbazi, M.-A.; Mathur, S.; et al. Designing of a Multifunctional 3D-Printed Biomimetic Theragenerative Aerogel Scaffold via Mussel-Inspired Chemistry: Bioactive Glass Nanofiber-Incorporated Self-Assembled Silk Fibroin with Antibacterial, Antiosteosarcoma, and Osteoinductive Properties. ACS Appl. Mater. Interfaces 2024, 16, 22809–22827. [Google Scholar] [CrossRef]
  136. Zhao, J.; Qiu, P.; Wang, Y.; Wang, Y.; Zhou, J.; Zhang, B.; Zhang, L.; Gou, D. Chitosan-based hydrogel wound dressing: From mechanism to applications, a review. Int. J. Biol. Macromol. 2023, 244, 125250. [Google Scholar] [CrossRef]
  137. Sarmah, D.; Rather, M.A.; Sarkar, A.; Mandal, M.; Sankaranarayanan, K.; Karak, N. Self-cross-linked starch/chitosan hydrogel as a biocompatible vehicle for controlled release of drug. Int. J. Biol. Macromol. 2023, 237, 124206. [Google Scholar] [CrossRef] [PubMed]
  138. Hu, Z.; Liu, D.; Wang, M.; Yu, C.; Han, Z.; Xu, M.; Yue, W.; Nie, G. β-Alanine enhancing the crosslink of chitosan/poly-(γ-glutamic acid) hydrogel for a potential alkaline-adapted wound dressing. Int. J. Biol. Macromol. 2023, 231, 123157. [Google Scholar] [CrossRef] [PubMed]
  139. Mu, M.; Li, X.; Tong, A.; Guo, G. Multi-functional chitosan-based smart hydrogels mediated biomedical application. Expert Opin. Drug Deliv. 2019, 16, 239–250. [Google Scholar] [CrossRef]
  140. Gou, D.; Qiu, P.; Hong, F.; Wang, Y.; Ren, P.; Cheng, X.; Wang, L.; Liu, T.; Liu, J.; Zhao, J. Polydopamine modified multifunctional carboxymethyl chitosan/pectin hydrogel loaded with recombinant human epidermal growth factor for diabetic wound healing. Int. J. Biol. Macromol. 2024, 274, 132917. [Google Scholar] [CrossRef]
  141. Oh, D.X.; Hwang, D.S. A biomimetic chitosan composite with improved mechanical properties in wet conditions. Biotechnol. Prog. 2013, 29, 505–512. [Google Scholar] [CrossRef] [PubMed]
  142. Zhang, X.; Hassanzadeh, P.; Miyake, T.; Jin, J.; Rolandi, M. Squid beak inspired water processable chitosan composites with tunable mechanical properties. J. Mater. Chem. B 2016, 4, 2273–2279. [Google Scholar] [CrossRef]
  143. Ryu, J.H.; Jo, S.; Koh, M.; Lee, H. Bio-Inspired, Water-Soluble to Insoluble Self-Conversion for Flexible, Biocompatible, Transparent, Catecholamine Polysaccharide Thin Films. Adv. Funct. Mater. 2014, 24, 7709–7716. [Google Scholar] [CrossRef]
  144. Edson, J.A.; Ingato, D.; Wu, S.; Lee, B.; Kwon, Y.J. Aqueous-Soluble, Acid-Transforming Chitosan for Efficient and Stimuli-Responsive Gene Silencing. Biomacromolecules 2018, 19, 1508–1516. [Google Scholar] [CrossRef] [PubMed]
  145. Kim, K.; Ryu, J.H.; Lee, D.Y.; Lee, H. Bio-inspired catechol conjugation converts water-insoluble chitosan into a highly water-soluble, adhesive chitosan derivative for hydrogels and LbL assembly. Biomater. Sci. 2013, 1, 783–790. [Google Scholar] [CrossRef]
  146. Qiao, H.; Sun, M.; Su, Z.; Xie, Y.; Chen, M.; Zong, L.; Gao, Y.; Li, H.; Qi, J.; Zhao, Q.; et al. Kidney-specific drug delivery system for renal fibrosis based on coordination-driven assembly of catechol-derived chitosan. Biomaterials 2014, 35, 7157–7171. [Google Scholar] [CrossRef]
  147. Sakono, N.; Nakamura, K.; Ohshima, T.; Hayakawa, R.; Sakono, M. Tyrosinase-mediated Peptide Conjugation with Chitosan-coated Gold Nanoparticles. Anal. Sci. 2018, 35, 79–83. [Google Scholar] [CrossRef]
  148. Samyn, P. A platform for functionalization of cellulose, chitin/chitosan, alginate with polydopamine: A review on fundamentals and technical applications. Int. J. Biol. Macromol. 2021, 178, 71–93. [Google Scholar] [CrossRef]
  149. Rahnama, H.; Khorasani, S.N.; Aminoroaya, A.; Molavian, M.R.; Allafchian, A.; Khalili, S. Facile preparation of chitosan-dopamine-inulin aldehyde hydrogel for drug delivery application. Int. J. Biol. Macromol. 2021, 185, 716–724. [Google Scholar] [CrossRef]
  150. Zhang, M.; Zhao, X. Alginate hydrogel dressings for advanced wound management. Int. J. Biol. Macromol. 2020, 162, 1414–1428. [Google Scholar] [CrossRef]
  151. Rastogi, P.; Kandasubramanian, B. Review of alginate-based hydrogel bioprinting for application in tissue engineering. Biofabrication 2019, 11, 042001. [Google Scholar] [CrossRef]
  152. Nagakura, T.; Hirata, H.; Tsujii, M.; Sugimoto, T.; Miyamoto, K.; Horiuchi, T.; Nagao, M.; Nakashima, T.; Uchida, A. Effect of viscous injectable pure alginate sol on cultured fibroblasts. Plast. Reconstr. Surg. 2005, 116, 831–838. [Google Scholar] [CrossRef] [PubMed]
  153. Schulz, A.; Gepp, M.M.; Stracke, F.; von Briesen, H.; Neubauer, J.C.; Zimmermann, H. Tyramine-conjugated alginate hydrogels as a platform for bioactive scaffolds. J. Biomed. Mater. Res. Part A 2019, 107, 114–121. [Google Scholar] [CrossRef] [PubMed]
  154. Yuan, N.; Shao, K.; Huang, S.; Chen, C. Chitosan, alginate, hyaluronic acid and other novel multifunctional hydrogel dressings for wound healing: A review. Int. J. Biol. Macromol. 2023, 240, 124321. [Google Scholar] [CrossRef]
  155. Raus, R.A.; Nawawi, W.M.F.W.; Nasaruddin, R.R. Alginate and alginate composites for biomedical applications. Asian J. Pharm. Sci. 2021, 16, 280–306. [Google Scholar] [CrossRef]
  156. Lan, L.; Ping, J.; Li, H.; Wang, C.; Li, G.; Song, J.; Ying, Y. Skin-Inspired All-Natural Biogel for Bioadhesive Interface. Adv. Mater. 2024, 36, e2401151. [Google Scholar] [CrossRef]
  157. Ye, Z.; Mao, Z. Research Progress on the Regulation of Structure and Antioxidant Properties of Polydopamine-Based Nano-materials and Their Biomedical Applications. Mater. China 2022, 41, 679–688. [Google Scholar] [CrossRef]
  158. Kashi, M.; Nazarpak, M.H.; Nourmohammadi, J.; Moztarzadeh, F. Study the effect of different concentrations of polydopamine as a secure and bioactive crosslinker on dual crosslinking of oxidized alginate and gelatin wound dressings. Int. J. Biol. Macromol. 2024, 277 Pt 3, 134199. [Google Scholar] [CrossRef]
  159. Rezk, A.I.; Obiweluozor, F.O.; Choukrani, G.; Park, C.H.; Kim, C.S. Drug release and kinetic models of anticancer drug (BTZ) from a pH-responsive alginate polydopamine hydrogel: Towards cancer chemotherapy. Int. J. Biol. Macromol. 2019, 141, 388–400. [Google Scholar] [CrossRef]
  160. Liang, M.; He, C.; Dai, J.; Ren, P.; Fu, Y.; Wang, F.; Ge, X.; Zhang, T.; Lu, Z. A high-strength double network polydopamine nanocomposite hydrogel for adhesion under seawater. J. Mater. Chem. B 2020, 8, 8232–8241. [Google Scholar] [CrossRef]
  161. Xu, J.; Wang, G.; Wu, Y.; Ren, X.; Gao, G. Ultrastretchable Wearable Strain and Pressure Sensors Based on Adhesive, Tough, and Self-healing Hydrogels for Human Motion Monitoring. ACS Appl. Mater. Interfaces 2019, 11, 25613–25623. [Google Scholar] [CrossRef] [PubMed]
  162. Montazerian, H.; Baidya, A.; Haghniaz, R.; Davoodi, E.; Ahadian, S.; Annabi, N.; Khademhosseini, A.; Weiss, P.S. Stretchable and Bioadhesive Gelatin Methacryloyl-Based Hydrogels Enabled by in Situ Dopamine Polymerization. ACS Appl. Mater. Interfaces 2021, 13, 40290–40301. [Google Scholar] [CrossRef] [PubMed]
  163. Wu, E.; Huang, L.; Shen, Y.; Wei, Z.; Li, Y.; Wang, J.; Chen, Z. Application of gelatin-based composites in bone tissue engineering. Heliyon 2024, 10, e36258. [Google Scholar] [CrossRef]
  164. Afewerki, S.; Sheikhi, A.; Kannan, S.; Ahadian, S.; Khademhosseini, A. Gelatin-polysaccharide composite scaffolds for 3D cell culture and tissue engineering: Towards natural therapeutics. Bioeng. Transl. Med. 2018, 4, 96–115. [Google Scholar] [CrossRef]
  165. Pei, X.; Zhang, H.; Zhou, Y.; Zhou, L.; Fu, J. Stretchable, self-healing and tissue-adhesive zwitterionic hydrogels as strain sensors for wireless monitoring of organ motions. Mater. Horizons 2020, 7, 1872–1882. [Google Scholar] [CrossRef]
  166. Lee, H.A.; Park, E.; Lee, H. Polydopamine and Its Derivative Surface Chemistry in Material Science: A Focused Review for Studies at KAIST. Adv. Mater. 2020, 32, e1907505. [Google Scholar] [CrossRef] [PubMed]
  167. Chen, Y.; Song, J.; Wang, S.; Liu, W. PVA-Based Hydrogels: Promising Candidates for Articular Cartilage Repair. Macromol. Biosci. 2021, 21, 2100147. [Google Scholar] [CrossRef]
  168. Sun, S.; Cui, Y.; Yuan, B.; Dou, M.; Wang, G.; Xu, H.; Wang, J.; Yin, W.; Wu, D.; Peng, C. Drug delivery systems based on polyethylene glycol hydrogels for enhanced bone regeneration. Front. Bioeng. Biotechnol. 2023, 11, 1117647. [Google Scholar] [CrossRef]
  169. Washington, M.A.; Balmert, S.C.; Fedorchak, M.V.; Little, S.R.; Watkins, S.C.; Meyer, T.Y. Monomer sequence in PLGA microparticles: Effects on acidic microclimates and in vivo inflammatory response. Acta Biomater. 2018, 65, 259–271. [Google Scholar] [CrossRef]
  170. Wu, Z.; Yuan, K.; Zhang, Q.; Guo, J.J.; Yang, H.; Zhou, F. Antioxidant PDA-PEG nanoparticles alleviate early osteoarthritis by inhibiting osteoclastogenesis and angiogenesis in subchondral bone. J. Nanobiotechnol. 2022, 20, 479. [Google Scholar] [CrossRef]
  171. Liu, Y.; Hong, H.; Xiao, Y.; Kwok, M.L.; Liu, H.; Tian, X.Y.; Choi, C.H.J. Dopamine Receptor-Mediated Binding and Cellular Uptake of Polydopamine-Coated Nanoparticles. ACS Nano 2021, 15, 13871–13890. [Google Scholar] [CrossRef] [PubMed]
  172. Sun, L.; Zheng, C.; Webster, T.J. Self-assembled peptide nanomaterials for biomedical applications: Promises and pitfalls. Int. J. Nanomed. 2016, 12, 73–86. [Google Scholar] [CrossRef] [PubMed]
  173. Qiang, W.; Li, W.; Li, X.; Chen, X.; Xu, D. Bioinspired polydopamine nanospheres: A superquencher for fluorescence sensing of biomolecules. Chem. Sci. 2014, 5, 3018–3024. [Google Scholar] [CrossRef]
  174. Hing, K.A. Bone repair in the twenty–first century: Biology, chemistry or engineering? Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 2004, 362, 2821–2850. [Google Scholar] [CrossRef]
  175. Raeburn, J.; Cardoso, A.Z.; Adams, D.J. The importance of the self-assembly process to control mechanical properties of low molecular weight hydrogels. Chem. Soc. Rev. 2013, 42, 5143–5156. [Google Scholar] [CrossRef]
  176. Liyanage, W.; Ardoña, H.A.M.; Mao, H.-Q.; Tovar, J.D. Cross-Linking Approaches to Tuning the Mechanical Properties of Peptide π-Electron Hydrogels. Bioconjug. Chem. 2016, 28, 751–759. [Google Scholar] [CrossRef]
  177. Maslovskis, A.; Guilbaud, J.-B.; Grillo, I.; Hodson, N.; Miller, A.F.; Saiani, A. Self-assembling peptide/thermoresponsive polymer composite hydrogels: Effect of peptide–polymer interactions on hydrogel properties. Langmuir 2014, 30, 10471–10480. [Google Scholar] [CrossRef]
  178. Adhikari, B.; Nanda, J.; Banerjee, A. Pyrene-containing peptide-based fluorescent organogels: Inclusion of graphene into the organogel. Chemistry 2011, 17, 11488–11496. [Google Scholar] [CrossRef] [PubMed]
  179. Cao, W.; Zhang, X.; Miao, X.; Yang, Z.; Xu, H. γ-Ray-responsive supramolecular hydrogel based on a diselenide-containing polymer and a peptide. Angew. Chem. Int. Ed. Engl. 2013, 52, 6233–6237. [Google Scholar] [CrossRef]
  180. Fichman, G.; Schneider, J.P. Dopamine Self-Polymerization as a Simple and Powerful Tool to Modulate the Viscoelastic Mechanical Properties of Peptide-Based Gels. Molecules 2021, 26, 1363. [Google Scholar] [CrossRef]
  181. Falcone, N.; Andoy, N.M.O.; Sullan, R.M.A.; Kraatz, H.-B. Peptide-Polydopamine Nanocomposite Hydrogel for a Laser-Controlled Hydrophobic Drug Delivery. ACS Appl. Bio Mater. 2021, 4, 6652–6657. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Two synthetic pathways of polydopamine: (A) Covalent polymerization pathway, (B) Non-covalent self-assembly pathway [21].
Figure 1. Two synthetic pathways of polydopamine: (A) Covalent polymerization pathway, (B) Non-covalent self-assembly pathway [21].
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Figure 2. Schematic representation of PDA nanocomposite hydrogel applied to bone defect repair.
Figure 2. Schematic representation of PDA nanocomposite hydrogel applied to bone defect repair.
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Figure 3. The mechanism of polydopamine-based modified hydrogels.
Figure 3. The mechanism of polydopamine-based modified hydrogels.
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Figure 4. Synthesis of PDA-coated magnesium calcium carbonate microspheres and thermally responsive hydroxybutyl chitosan (HBC) dual responsive hydrogel used for near infrared (NIR) triggered continuous delivery of aspirin (Asp) and BMP-2 to promote in situ calvaria bone regeneration. Adapted with permission from Ref. [82]. Copyright 2022 Carbohydrate polymers.
Figure 4. Synthesis of PDA-coated magnesium calcium carbonate microspheres and thermally responsive hydroxybutyl chitosan (HBC) dual responsive hydrogel used for near infrared (NIR) triggered continuous delivery of aspirin (Asp) and BMP-2 to promote in situ calvaria bone regeneration. Adapted with permission from Ref. [82]. Copyright 2022 Carbohydrate polymers.
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Figure 5. Osteogenic differentiation analysis: (A)Alkaline phosphatase (ALP) staining showed the distribution and activity of BMSC in alginate and alginate DA fibrous matrices after 14 days of osteogenic induction. (B) ALP activity of BMSC cultured in alginate and alginate dopamine fiber matrices on days 7 and 14 of osteoinduction; data shown as mean ± SD (n = 3), “*” indicates significant difference with p < 0.05. Adapted with permission from Ref. [83]. Copyright 2016 Materials Science and Engineering: C.
Figure 5. Osteogenic differentiation analysis: (A)Alkaline phosphatase (ALP) staining showed the distribution and activity of BMSC in alginate and alginate DA fibrous matrices after 14 days of osteogenic induction. (B) ALP activity of BMSC cultured in alginate and alginate dopamine fiber matrices on days 7 and 14 of osteoinduction; data shown as mean ± SD (n = 3), “*” indicates significant difference with p < 0.05. Adapted with permission from Ref. [83]. Copyright 2016 Materials Science and Engineering: C.
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Figure 6. Antibacterial activity analysis: No inhibition zone against * Salmonella * was observed for nanosilver that was not modified with dopamine (A). However, alginate dopamine beads and fibers coated with nanosilver exhibited significant inhibition zones against both Gram-positive and Gram-negative bacteria (B,C). Adapted with permission from Ref. [83]. Copyright 2016 Materials Science and Engineering: C.
Figure 6. Antibacterial activity analysis: No inhibition zone against * Salmonella * was observed for nanosilver that was not modified with dopamine (A). However, alginate dopamine beads and fibers coated with nanosilver exhibited significant inhibition zones against both Gram-positive and Gram-negative bacteria (B,C). Adapted with permission from Ref. [83]. Copyright 2016 Materials Science and Engineering: C.
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Figure 7. (A) Preparation of bilayer hydrogel for cartilage defect repair. (a) Gelatin methacryloyl (GelMA) was mixed with polydopamine (PDA) to prepare the upper layer hydrogel for cartilage defect repair. (b) Ca2+ GelMA was mixed with PO43− GelMA to mineralize hydroxyapatite (HA) in situ, to prepare the lower layer hydrogel for subchondral bone repair. (c) Polymerization to generate bilayer hydrogels. (d) Schematic of osteochondral defect repair. (B) Gross morphological examination of osteochondral defects in the knee joint of rabbits at 6 and 12 weeks after operation was performed. Adapted with permission from Ref. [85]. Copyright 2022 Advanced Healthcare Materials.
Figure 7. (A) Preparation of bilayer hydrogel for cartilage defect repair. (a) Gelatin methacryloyl (GelMA) was mixed with polydopamine (PDA) to prepare the upper layer hydrogel for cartilage defect repair. (b) Ca2+ GelMA was mixed with PO43− GelMA to mineralize hydroxyapatite (HA) in situ, to prepare the lower layer hydrogel for subchondral bone repair. (c) Polymerization to generate bilayer hydrogels. (d) Schematic of osteochondral defect repair. (B) Gross morphological examination of osteochondral defects in the knee joint of rabbits at 6 and 12 weeks after operation was performed. Adapted with permission from Ref. [85]. Copyright 2022 Advanced Healthcare Materials.
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Figure 8. (A) H&E staining of decalcified gel matrix sections with cell laden microcarriers: PDA treated (control), VEGF encapsulated, BMP-2 conjugated, and VEGF encapsulated microcarriers with BMP-2 after 6 weeks of subcutaneous implantation. (B) Real-time PCR analysis of RUNX2, OCN, and ALP expression after 6 weeks of subcutaneous implantation. Data are presented as means ± standard deviations. Modified from Dashtimoghadam et al. [87]. (2020) under the terms of the Creative Commons Attribution International License (CCBY4.0).
Figure 8. (A) H&E staining of decalcified gel matrix sections with cell laden microcarriers: PDA treated (control), VEGF encapsulated, BMP-2 conjugated, and VEGF encapsulated microcarriers with BMP-2 after 6 weeks of subcutaneous implantation. (B) Real-time PCR analysis of RUNX2, OCN, and ALP expression after 6 weeks of subcutaneous implantation. Data are presented as means ± standard deviations. Modified from Dashtimoghadam et al. [87]. (2020) under the terms of the Creative Commons Attribution International License (CCBY4.0).
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Figure 9. The osteoblastic ability of the AgNPs/PDA gel detected by Alizarin red staining: Alizarin red staining shows osteoblastic activity of AgNPs/PDA gel. (A) Cells on a 2D plate. (B) Cells on a 2D plate with osteogenic inducer. (C) Cells on the gel. (D) Cells on the gel with osteogenic inducer. Green arrows indicate calcium nodes. Scale bar: 250 μm. Adapted with permission from Ref. [105]. Copyright 2018 Materials Science and Engineering: C.
Figure 9. The osteoblastic ability of the AgNPs/PDA gel detected by Alizarin red staining: Alizarin red staining shows osteoblastic activity of AgNPs/PDA gel. (A) Cells on a 2D plate. (B) Cells on a 2D plate with osteogenic inducer. (C) Cells on the gel. (D) Cells on the gel with osteogenic inducer. Green arrows indicate calcium nodes. Scale bar: 250 μm. Adapted with permission from Ref. [105]. Copyright 2018 Materials Science and Engineering: C.
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Figure 10. Antibacterial activity of AgNPs/PDA gel: (A,C) S. aureus groups. (B,D) E. coli groups. (C,D) Statistical analysis of antibacterial ring diameter. Data are presented as mean ± standard deviation (SD). Adapted with permission from Ref. [105]. Copyright 2018 Materials Science and Engineering: C.
Figure 10. Antibacterial activity of AgNPs/PDA gel: (A,C) S. aureus groups. (B,D) E. coli groups. (C,D) Statistical analysis of antibacterial ring diameter. Data are presented as mean ± standard deviation (SD). Adapted with permission from Ref. [105]. Copyright 2018 Materials Science and Engineering: C.
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Figure 11. Rheological studies of the 0.5 wt.% MAX1 dopamine gel system. (A) Rheological analysis of 0.5 wt.% MAX1 gel 3 days post gelation with varying dopamine concentrations. Left bar (I) shows the initial G’ value before shear thinning (1000% strain, 30 s), and right bar (II) shows the recovered G’ value 10 min after shear thinning. Data are presented as means ± standard deviations. (B) Time sweep measurements of 0.5 wt.% MAX1 gel without dopamine (black) and with 5 mM dopamine (red), tracking G and G” (dark and light, respectively) over time at 37 °C, pH 7.4. (C) Presheared G and G values of preformed 0.5 wt.% MAX1 gel. Modified from Fichman et al. [180]. (2021) under the terms of the Creative Commons Attribution International License (CCBY4.0).
Figure 11. Rheological studies of the 0.5 wt.% MAX1 dopamine gel system. (A) Rheological analysis of 0.5 wt.% MAX1 gel 3 days post gelation with varying dopamine concentrations. Left bar (I) shows the initial G’ value before shear thinning (1000% strain, 30 s), and right bar (II) shows the recovered G’ value 10 min after shear thinning. Data are presented as means ± standard deviations. (B) Time sweep measurements of 0.5 wt.% MAX1 gel without dopamine (black) and with 5 mM dopamine (red), tracking G and G” (dark and light, respectively) over time at 37 °C, pH 7.4. (C) Presheared G and G values of preformed 0.5 wt.% MAX1 gel. Modified from Fichman et al. [180]. (2021) under the terms of the Creative Commons Attribution International License (CCBY4.0).
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Figure 12. Morphological characterization map of nanocomposite hydrogels: TEM, and AFM images of (a) C14-FF gels alone, (b) C14-FF + rifampicin, (c) C14-FF + PDNP, and (d) C14-FF + PDNP + rifampicin. Modified from Falcone et al. [181]. (2021) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
Figure 12. Morphological characterization map of nanocomposite hydrogels: TEM, and AFM images of (a) C14-FF gels alone, (b) C14-FF + rifampicin, (c) C14-FF + PDNP, and (d) C14-FF + PDNP + rifampicin. Modified from Falcone et al. [181]. (2021) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
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Figure 13. Passive release of rifampicin from the C14-FF hydrogel alone versus the nanocomposite hydrogel with PDNP, and the growth of Escherichia coli after laser induced release (ac). Data are presented as means ± standard deviations. Modified from Falcone et al. [181]. (2021) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
Figure 13. Passive release of rifampicin from the C14-FF hydrogel alone versus the nanocomposite hydrogel with PDNP, and the growth of Escherichia coli after laser induced release (ac). Data are presented as means ± standard deviations. Modified from Falcone et al. [181]. (2021) under the terms of the Creative Commons Attribution International License (CC BY 4.0).
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Table 1. Recent advances in PDA-based hydrogel delivery system for bone defect repair.
Table 1. Recent advances in PDA-based hydrogel delivery system for bone defect repair.
Type of Composite HydrogelTypes of Cells/BacteriaType of Animal ModelDrugs/Growth Factors/OthersAdvantagesDisadvantagesReference
PDA/Hydroxybutyl chitosan hydrogelhBMMSCsSD ratsAspirinDual responsive propertiesComplex processingWan et al. [82]
PDA/alginate hydrogelBMSCs/Silver NanoparticlesAntibacterial/anti-infective propertiesInsufficient mechanical strengthZhang et al. [83]
PDA/Alginate-allylated double-cross-linked hydrogelsMG63
rBMSCs
/DOXFast kinetic response/High UV cross-linking conversion efficiency/Excellent mechanical propertiesInsufficient stability of drug releaseChen et al. [84]
GelMA-PDA/HA hydrogelBMSCsNew Zealand white rabbitsBMP-2
TGF-β3
Excellent osteochondral repairReducing degradation speedGan et al. [85]
GelMA/PMMA/PDA hydrogelBMSCsBALB/c rats/Good biocompatibility/degradation propertiesLocal overheatingWu et al. [86]
PLGA-PDA-/Alginate-RGD hydrogelBMSCs
HUVECs
HELA
MC3T3-E1
Fischer 344 rats
SD rats
BMP-2
VEGF
BP
Doxorubicin
Hydrochloride
Precise and timely drug releaseComplex processingDashtimoghaamet al. [87]
Polyvinyl alcohol (PVA)/PDA@HAP hydrogelBMSCsSD ratsSilver NanoparticlesHAP Long-lasting antimicrobial effectInduction of cytotoxicity by silver nanoparticlesLi et al. [88]
PDA/Hyaluronic acid methacrylate hydrogel MPsBMSCsSD rats
Rabbits
Barium titanate nanoparticles
Stem cell recruitment peptides
Precise electrical stimulationPoor stabilityHan et al. [89]
PDA hydrogelhBMSCsSD ratsCNT
PLA
High mechanical strengthLarge manufacturing scaleSun et al. [90]
PDA@E2/HA/GelMA/Gel hydrogelBMSCs/Employing estradiol
BMSCs
Adaptation of complex defectsDegradation rate/trigger conditions need to be optimizedChen et al. [91]
MSN@pDA/Chitosan (CS) hydrogelSMSCsSD rats
Rabbits
TGF-β3
IGF-I
PDGF-BB
Activation of endogenous cartilage repairInsufficient stabilityLi et al. [92]
PDA/Gelatin methacrylate/sodium alginate methacrylate (GA) hybrid hydrogelHUVECs
MC3T3-E1
SD ratsDFO
PO43−
Improving the microenvironment of bone regenerationInsufficient biocompatibility/photothermal efficiencyWu et al. [93]
PDA/Hydroxypropyl chitosan/Gelatin (HG) hydrogelHUVECs
MC3T3-E1
BALB/c ratsaFGF
Ti3C2Tx Mxene
nanosheets
Accelerating critical bone defect healingInadequate biosecurity/limited demand for light control devicesWu et al. [94]
KGN@PDA/UPy hydrogelBMSCsRabbitsKGN
miRNA@CaP NPs
Stable mechanical properties/strong self-healing abilityComplex forming process/insufficient transfection efficiencyKang et al. [95]
PDA/ PEEK/Gelatin hydrogelhMSCs/BMP-2Enhanced osteogenic differentiation./Improved bio-inertness of the materialLimited drug loadingZhang et al. [96]
PDA/Fpolyacrylamide/Silk fibroin hydrogelBMSCs
HUVECs
SD ratsBMP-2DFOExcellent interfacial adhesion/structural toughness/mechanical stiffness.Need for multiple photothermal interventions, large implants to trigger foreign body reactions Li et al. [97]
BML@β-TCP/PDA carboxymethyl chitosan hydrogelMC3T3-E1SD ratsBML-284Multipurpose bone repairHigh preparation costsWu et al. [98]
GPEGD/PDA hydrogelMC3T3-E1SD ratsBMP-2
Heparin
Excellent mechanical properties/biocompatibilityLimited cell infiltration/Insufficient stability of ROS scavengersWu et al. [99]
PDA@zeolitic imidazolate framework-8/Soft matrix hydrogelMC3T3-E1
RAW264.7
HUVECs
SD ratsZn2+Good structural stability/mechanical supportThe complex diabetic microenvironment impairs the therapeutic effectWu et al. [100]
PDA/Al/GP/Fibrin hydrogelsEMSCsSD ratsAl
GP
Dual functions of osteoinduction and immunomodulationAlendronate affects the balance of bone remodelingShi et al. [101]
Methacrylated silk fibroin (SFMA)/PDA hydrogelHUVECs
BMSCs
SD ratsMAPExhibits good biocompatibility/physicochemical propertiesUneven distribution of photothermal agent/local overheatingMa et al. [102]
Alginate methacrylate/Alginate/PDA hydrogelMC3T3-E1SD ratsTi3C2 MXene nanosheetsGood biocompatibility/osteogenic activity/immune-regulatory functionsPhototherapy produces free radicals that damage cellsWu et al. [103]
PDA/Polysaccharide chitin hydrogelMC3T3-E1
BMSCs
Wistar male ratsCu2+
Nano HAP
High biocompatibility/Significant osteogenic activity.Insufficient interfacial bonding strengthHuang et al. [104]
PDA/Polyethylene hydrogel (PEG)MC3T3-E1SD ratsAgNPsMineralization/anti-infection dual functionReducing the elasticity of hydrogelXu et al. [105]
PDA/Chitosan/Gelatin hydrogelHUVECs
MC3T3-E1
RAW 264.7
SD ratsHydroxyapatite
BaTiO3 NPs
Excellent immunomodulation/angiogenesis/osteogenesis/suitable for combat wound repairComplex material processingWu et al. [106]
PDACS/PCL/HydrogelHUVECs
WJMSCs
/HUVECs
WJMSCs
Synergized to promote osteogenesis/vascularizationCalcium silicate degradation products affect pH/limited microstructure controlChen et al. [107]
Oxidized sodium alginate (OSA)/Gelatin (Gel)/PDA-nHA hydrogelBMSCsJapanese big-ear white rabbitsnHAInjectable/easy to operateLong-term stability of nano-hydroxyapatite (nHA) in vivo is insufficientLiu et al. [108]
CGH/PDA@HAP hydrogelBMSCsSD ratsGallic acid
Hydroxyapatite
Enhanced antibacterial and osteogenic synergyGeneration of acidic degradation productsPang et al. [109]
Characterization of the fucoidan/PDA hydrogelPDLSCs//Enhanced osteogenic potentialQuality control of fucoidan sulfate was lowKwack et al. [110]
Polyacrylamide/PDA hydrogelMG-63//Matrix stiffness targets osteosarcoma cell apoptosisStiffness parameters need to be highly precise/difficult to adjust in clinical applicationDeng et al. [111]
Xanthan gum-PDA hydrogelBMSCsSD ratsSDF-1α
Mg2+
Excellent injectability/mechanical propertiesHigh SDF-1α inactivationLi et al. [28]
OSA-GelDA@ACP/DA/Ag hydrogel//ACP
DA
Ag+
Composite hydrogel combines tissue adhesion and anti-infection functionsThe hydrogel flexibility/bond strength decreasedZhong et al. [112]
PDA/Chondroitin sulfate hydrogelrBMSCsNew Zealand rabbitsSDF-1αSustained-release SDF-1αLack of control over release kineticsWu et al. [113]
ALG/GelAGE-PDA@DOX hydrogelsrBMSCs
MG 63
/Sr2+
DOX
Synergistic effect of chemotherapy and photothermal therapy (PTT)Degree of cross-linking affects the stability of drug releaseChen et al. [84]
PDA/GMS/Osteogenic hydrogelP. gingivalisSD ratsAmino antibacterial nanoparticle
Magnetic nanoparticles
Precision antimicrobial therapyMagnetic field conditioning devices limit clinical applicationsZhou et al. [114]
PDA/Nano-hydroxyapatite (nHAP) hydrogelMC3T3-E1/PEEK
Aspirin
Good biocompatibility/compressive strength/modulusPoor cell adhesion to the inert surface of PEEKLi et al. [115]
CS/PDA hydrogelHUVECs/DFOEnhanced bond strength/angiogenic effectShort half-life of deferoxamine/frequent injections requiredLiu et al. [116]
BNP-PEDOT-PSF-AG hydrogelPDLSCsSD ratsBovine serum
albumin nanoparticles
Hydrogen sulfide
Promoting alveolar bone regeneration/reversing inflammatory microenvironment under diabetic conditionsDifficulty in controlling the release of H2S gasFang et al. [117]
Alginate/TOCNF/PDA hydrogelMC3T3-E1/TOCNFs
PDANPs
High osteogenic activityLow structural fidelity after printingIm et al. [118]
GO-PHA-CPs hydrogelMC3T3-E1SD ratsCPsExhibits excellent injectability/adhesion/antioxidant activity/osteoinductive propertiesLimited self-repair capacity/degradation rate mismatch with bone formation rateMa et al. [119]
DA-nano-hydroxyapatite hydrogel4T1
BMSCs
BALB/c miceDDPSynergistic photothermal anti-tumor/bone regeneration capabilitiesPhotothermal agents are potentially toxicLuo et al. [120]
MCG-HG-PLGA-PD-B hydrogelATDC5
MC3T3-E1
/BMP-7Promoting Structural Bionicity in Cartilage RegenerationInsufficient scaffold porosity connectivityJung et al. [121]
Gellan gum/PDA hydrogelMC3T3-E1/ALPPolydopamine enhances the efficiency of mineralizationIncreased material brittleness/complex preparation processDouglas et al. [122]
PF-127/HAMA/M@S (PH/M@S) hydrogelrBMSCs
HUVEC
RAW264.7
MiceM@S NPsCost-effective/easy to synthesize/possesses multiple therapeutic capabilitiesNanoparticles prone to leakageLiu et al. [123]
PDA/LC hydrogelBMSCs
E. coli
S. aureus
SD rats/Excellent osteogenic activity/angiogenic capacity/antimicrobial effectsChitosan causes allergic reactions/complex preparationLi et al. [124]
Gel-PHA hydrogelMC3T3-E1SD ratsnHAEnhanced mechanical and osteogenic properties of gelatin hydrogelsReduced hydrogel elasticityMa et al. [125]
T/DOP-IL 4/CG-RGD hydrogelBMSCs/IL-4
RGD peptide
IL-4 and RGD synergistically regulate the osteoimmune microenvironmentIL-4 short half-life/RGD overexpressionLi et al. [126]
PDA/Gel-PAA hydrogelBMSCsNew Zealand rabbitsTGF-β3Enhances the toughness and cell affinity of PAA hydrogelsCatechol oxidative cross-linking is irreversible/affects controllability of degradationYan et al. [127]
AD/CS/RSF/EXO hydrogelBMSCsSD ratsExosomesExcellent mechanical properties/biodegradability/biocompatibility/the abilityLow efficiency in exosome extraction and loadingZhang et al. [128]
CTP-SA/TiO2@PDA hydrogelHUVEC
BMSCs
Staphylococcus aureus
Escherichia coli
Streptococcus mutans
SD ratsCu2O
TiO2 NPs
Enhanced antimicrobial activityInsufficient mechanical propertiesXu et al. [129]
PDA@SiO2-PRF hydrogelBMSCsSD ratsPRFMulti-level regulation of microenvironmentProteins are prone to degradation/short shelf lifeRen et al. [130]
Chitosan/ Polydopamine/NO-PVA hydrogelMRSA
MC3T3-E1
SD ratsTi-RP/PCP/RSNO
NO
With combined photothermal/immunotherapyPhotothermal effect damages surrounding healthy tissueLi et al. [131]
PnP-iPRF hydrogelBMSCs
RAW 264.7
Ratsi-PRFMultiple pathways regulate the microenvironmentImmunogenic risk has not been completely ruled outLi et al. [132]
SP@MX/GelMA hydrogelMG-63
MC3T3-E1
Kunming miceTobramycinSignificantly enhances the initial adhesion and proliferation of cellsMXene nanosheets trigger inflammationYin et al. [133]
Gelatin-Silkfibroin-Oxidized dextran/PLLA-PLGA-PCL/PDA hydrogelBMSCsSD ratsKartogenin
P24 peptides
Excellent cell compatibility/Dual-layer scaffolds synergistically repair osteochondral defectsWeak interfacial bonding strength between the two layersZheng et al. [134]
SFO-TA-BGNF-PDA hydrogelMG-63/Bioactive glassIntegrated antimicrobial activity/antiosteosarcoma properties/osteoinduction of multiple functionsAerogel has low mechanical strength and is not suitable for load-bearing applicationsAbie et al. [135]
Abbreviations: hBM(M)SCs, human bone marrow mesenchymal stem cells; MG63, human osteosarcoma cells; rBMSCs, rat bone mesenchymal stem cells; BMSCs, bone marrow mesenchymal stem cells; HUVECs, human umbilical vein endothelial cells; HELA, human cervical cancer cell; MC3T3-E1, mouse embryo osteoblast precursor cells; hMSCs, human mesenchymal stem cells; RAW264.7, murine monocyte-macrophage leukemia cells; EMSCs, ecto-mesenchymal stem cells; WJMSCs, human Wharton’s jelly mesenchymal stem cells; PDLSCs, periodontal ligament stem cells; P. gingivalis, Porphyromonas gingivalis; 4T1, mouse breast cancer cells; ATDC5, mouse chondrocyte; E. coli, Escherichia coli; S. aureus, Staphylococcus aureus; MRSA, Methicillin-resistant staphylococcus aureus; BMP-2, bone morphogenetic protein-2; DOX, doxorubicin; TGF-β3, transforming growth factor-β3; VEGF, vascular endothelial growth factor; BP, black phosphorus; HAP, hydroxyapatite; CNT, carbon nanotube; PLA, polylactic acid; IGF-I, insulin-like growth factors; PDGF-BB, platelet-derived growth factor-BB; PO43−, phosphate; aFGF, acid fibro-blast growth factor; KGN, kartogenin; miRNA@CaP NPs, microRNA@calcium phosphate nanoparticles; DFO, deferoxamine; BML-284, wnt agonist 1; Zn2+, zinc ion; Al, aluminum; GP, genipin; MAP, magnesium ascorbyl phosphate; Ti3C2 MXene nanosheets, titanium carbide MXene nanosheets; Cu2+, cupric ion; Nano HAP, nano-hydroxyapatite; AgNPs, silver nanoparticles; BaTiO3 NPs, barium titanate nanoparticles; nHA, nanohydroxyapatite; SDF-1α, stromal cell-derived factor-1α; Mg2+, magnesium ion; ACP, amorphous calcium phosphate; DA, dopamine; Ag+, silver ion; Sr2+, strontium ions; PEEK, polyetheretherketone; TOCNFs, tempo-oxidized cellulose nanofibrils; PDANPs, polydopamine nanoparticles; CPs, bioactive cod peptides; DDP, cisplatin; BMP-7, bone morphogenetic protein-7; ALP; alkaline phosphatase; M@SNPs, spermidine-modified mesoporous polydopamine nano-particles; IL-4, interleukin-4; Cu2O, cuprous oxide; TiO2NPs, titanium dioxide nanoparticles; PRF, platelet-rich fibrin; Ti-RP/PCP/RSNO, titanium implant; NO, nitric oxide; i-PRF, injectable platelet-rich fibrin.
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Li, X.; Tang, J.; Guo, W.; Dong, X.; Cao, K.; Tang, F. Polydopamine Nanocomposite Hydrogel for Drug Slow-Release in Bone Defect Repair: A Review of Research Advances. Gels 2025, 11, 190. https://doi.org/10.3390/gels11030190

AMA Style

Li X, Tang J, Guo W, Dong X, Cao K, Tang F. Polydopamine Nanocomposite Hydrogel for Drug Slow-Release in Bone Defect Repair: A Review of Research Advances. Gels. 2025; 11(3):190. https://doi.org/10.3390/gels11030190

Chicago/Turabian Style

Li, Xiaoman, Jianhua Tang, Weiwei Guo, Xuan Dong, Kaisen Cao, and Fushan Tang. 2025. "Polydopamine Nanocomposite Hydrogel for Drug Slow-Release in Bone Defect Repair: A Review of Research Advances" Gels 11, no. 3: 190. https://doi.org/10.3390/gels11030190

APA Style

Li, X., Tang, J., Guo, W., Dong, X., Cao, K., & Tang, F. (2025). Polydopamine Nanocomposite Hydrogel for Drug Slow-Release in Bone Defect Repair: A Review of Research Advances. Gels, 11(3), 190. https://doi.org/10.3390/gels11030190

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