Epicatechin Derivatives in Tissue Engineering: Antioxidant,Anti-Inflammatory,Regenerative Use

Abstract

Epicatechin (EC)-based derivatives have garnered significant attention for their powerful antioxidant, anti-inflammatory, anticancer, and antibacterial properties, all of which are attributed to the phenolic hydroxyl groups in their structure. These compounds are promising in regenerative medicine, particularly as bioactive components in scaffolds. This review provides an in-depth analysis of the mechanisms by which EC-based materials enhance tissue repair, examining their application in various scaffold forms, such as hydrogels, nanoparticles, and nanofibers. This study also addresses the challenges of stability and bioavailability associated with ECs and proposes encapsulation techniques to overcome these barriers. The potential clinical benefits of ECs in regenerative medicine and their role in fostering advancements in tissue engineering are discussed, making this review a valuable resource for guiding future studies on the integration of ECs into clinical practice.

Impact Statement

This comprehensive review underscores the transformative potential of EC-based derivatives in advancing tissue engineering. By examining the antioxidant, anti-inflammatory, antibacterial, and anticancer properties of ECs, we highlight their promising application in bioactive scaffolds to support tissue repair and regeneration. Key challenges such as stability and bioavailability are addressed, along with innovative encapsulation and scaffold integration strategies that increase EC efficacy. These findings can guide future research and clinical applications, positioning ECs as vital components in the development of next-generation therapeutic scaffolds for regenerative medicine and precision health care.

Keywords

epicatechin derivatives tissue engineering tissue regeneration mechanism

Introduction

Tissue engineering harnesses advanced techniques from both biological science and engineering to improve compromised tissue functionality. The meticulous choice of appropriate scaffold materials, cell types, and bioactive compounds is of paramount importance in emulating the characteristics of the native extracellular matrix (ECM).^1–3

In addition to maintaining an appropriate environment, the scaffold can also serve as a reservoir for soluble bioactive molecules, releasing them in a controlled manner.⁴ Herbal extracts contain active ingredients such as polyphenols, saponins, and terpenoids, which, when combined with biomaterials, enhance physicochemical properties such as microstructure, wetting properties, and biodegradation behavior.⁵ As a result, the surrounding environment that interacts with the cell plays a crucial role in determining the biological response.⁶

Polyphenol compounds, including epicatechins (ECs), have been shown to have antioxidant, anti-inflammatory, immunoregulatory, vascular strengthening, and antithrombotic effects in various experimental models.^7,8 ECs are commonly present in various sources, including strawberries, apples, red wine, green or black tea, grapes, and cocoa.^9–14 The daily consumption of foods rich in ECs provides health benefits. The flavanols in cocoa help reduce inflammation by blocking the production of inflammatory substances.¹⁵

The structure and function of ECs have captured the attention of the tissue engineering field because of their capacity to engage in covalent and noncovalent interactions with biomacromolecules. These interactions can significantly enhance the biological activities of materials. These compounds can interact with biomolecules that contain multiple phenolic moieties. As a result, the incorporation of polyphenols can create a more biocompatible and bioactive scaffold.^8,16 Nanoencapsulation, hydrogel formation, and electrospinning are techniques used in advance to prepare EC-based biomaterials to treat inflammatory diseases.^7,9,17–21

Currently, studies on the use of ECs as bioactive components in scaffolds are limited. Moreover, the properties of the scaffold depend on the type of tissue, highlighting the challenges in tissue engineering.²² Most scientific literature focuses on EC supplementation rather than investigating its behavior as a bioactive component in scaffolds.^23–26 This result could be partly explained by the poor stability of flavonoids.²⁷ Overall, (-)-epigallocatechin-3-gallate (EGCG) and catechin (CAT), which are part of a group of flavonoids, have been studied more as bioactive components in scaffolds than ECs.^28–30

Recently, Yong et al.²⁷ functionalized ECs and EGCG with dialdehyde starch. The results demonstrated that EGCG was more unstable than EC was, but EGCG could scavenge free radicals more efficiently than could EC. On the one hand, Ares et al.³¹ reported that CAT and EC have the same antimicrobial activity but increase in response to EGCG, and the inhibition of digestive enzymes was more significant for EGCG and ECs than for CAT. These findings may explain why there are fewer studies on ECs as bioactive components in scaffolds.

Furthermore, Alves et al.³ constructed biomembrane scaffolds containing EGCG and EC and demonstrated that both components have promising biological effects on the repair process. Thus, the interaction of ECs could be further explored to expand the application of EC-based derivatives. As such, this review offers a comprehensive and up-to-date overview of current knowledge and future directions for the use of ECs in tissue engineering. Specifically, we examined its role as a bioactive compound in scaffolds, demonstrating antioxidative, anti-inflammatory, and immunoregulatory properties. These attributes position EC as a promising candidate for the development of techniques to create substrates that mimic the ECM. Our review aims to benefit researchers, students, and practitioners in various fields, including biomedical engineering, pharmacology, biotechnology, and medicine, by providing information on the latest advancements and applications of ECs in tissue engineering and elucidating the underlying mechanisms and challenges involved.

Methods

This study performed a meta-analysis to assess the effectiveness of ECs as bioactive agents in scaffolds for tissue engineering applications, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.³² The analysis focused on determining the antibacterial and anticancer activities of ECs via in vitro tests, evaluating EC bioaccessibility under simulated gastrointestinal conditions, and exploring the effects of ECs on skin regeneration via cellular and animal models. Data were gathered from PubMed, Web of Science and Scopus from April–May 2024, with the comprehensive search strategy outlined in the Supplementary Data S1.

For data pooling, random effects models were employed to accommodate expected variations across studies, allowing for generalizable results. Standardized mean differences and 95% confidence intervals were calculated for continuous data to facilitate comparisons. Heterogeneity was quantified via I² and tau-squared (τ²) statistics, with substantial heterogeneity addressed through subgroup and sensitivity analyses on the basis of scaffold type and application area. This approach ensured that the findings accounted for the variability among studies, enhancing the robustness and reliability of conclusions drawn about the role of ECs in tissue engineering.

Statistical analysis

For the statistical analysis of continuous data, we compared the viability of the anticancer activity scaffolds with and without EC via the mean ± standard deviation (SD). Dose–response analyses were necessary to evaluate the effects of varying concentrations of EC. Specifically, the antibacterial activity was assessed by measuring the zone of inhibition in the scaffolds with and without EC against E. coli and S. aureus. The linearity of the dose–response relationship was evaluated in the study by Snoussi et al.³³

In addition, the IC₅₀ values were analyzed to determine the viability of the skin cells, considering different cell lines as subgroups. To evaluate the release profiles, the percentage release of EC was analyzed under simulated gastric conditions, with subgroups categorized as oral, gastric, and intestinal. The statistical analysis was conducted via R software (version 4.4.0). The data for the different analyses are summarized in Supplementary Tables S1, S2, S3, S4, S5 and S6.

EC-Based Derivatives: Chemical Properties and Mechanisms of Action

Chemical properties of ECs

The chemical structure of ECs consists of two aromatic rings (A and B) connected through a pyran ring or an oxygen heterocyclic ring (Fig. 1).^34,35 Mendoza–Wilson et al.³⁶ studied the molecular properties of ECs and revealed that their structure is not planar, with a twist of −45.77° between ring B and the pyran ring; therefore, Anitha et al.³⁷ reported a torsion angle of −33°.

FIG. 1.

Schematic representation of key interaction types between ECs and scaffold materials. The chemical structures illustrate the various bonds formed by ECs in different applications: hydrogen bonding, covalent bonding and coordination bonds. EC, epicatechin.

The nonplanarity of flavonoids predicts low reactivity; therefore, their antioxidant potential is similar to that of quercetin, which is a flavonoid with great antioxidant activity.^36–38 The A ring containing a meta di-hydroxyl group clearly has a distributed charge density, indicating that it is a highly active site for antioxidant activity.³⁹ Nevertheless, the quantity of galloyl and hydroxyl (OH) groups in CAT molecules plays a significant role in determining their antioxidant properties. A greater number of hydroxyl groups typically leads to greater antioxidant activity. Therefore, compared with ECs, EGCG has stronger antioxidant effects.⁴⁰ Table 1 summarizes the comparative properties and interactions of ECs, CAT, and EGCG.

Table 1.

Comparative Properties and Interactions of Epicatechin, Catechin, and Epigallocatechin-3-Gallate

Properties	ECs	CAT	EGCG	Reference
Reactivity/nonplanarity	Nonplanar low reactivity	Nonplanar structure comparable to EC	Nonplanar structure high reactivity	^36,38,40,41
Antioxidant activity	Effective radical scavenger due to HAT^[1] and SPLET^[2] mechanisms	Comparable to EC	Stronger antioxidant due to high -OH content	^36,38,40,41
Main interactions	Hydrogen bonding, van der Waals.	Hydrogen bonding	Metal coordination, π–π stacking.	^36,38,40,41

The presence of hydroxyl groups at the 5, 7, 3, 3′, and 4’ positions enables ECs to interact with lipids and proteins, allowing for various binding mechanisms that support their therapeutic applications in tissue engineering.^35,42 In addition, ECs display intrinsic fluorescence at approximately 312 nm, and when interacting with proteins, this interaction causes a structural rearrangement that enhances the fluorescence phenomenon.⁴³

Wang et al.⁴⁴ prepared hydroxypropyl-β-cyclodextrin (HP-β-CD)/EC clathrate compounds and reported that HP-β-CD traps ECs mainly through hydrophobic interactions, van der Waals forces, or hydrogen bonds. The interaction of ECs with other molecules, such as malvidin-3-O-glucoside or ovotransferrin, is driven primarily by π–π stacking, hydrophobic bonds, and van der Waals forces. The aromatic rings in ECs increase the binding affinity through π stacking interactions, while alkyl–π interactions also contribute, especially in complexes with caffeic acid.^41,45,46

Polyphenols can bind to proteins through covalent interactions, although data on this topic are limited. In the presence of oxygen, ECs oxidize into o-quinone structures via enzymatic or nonenzymatic reactions. These o-quinones, which are strong electrophiles, can covalently bond with nucleophilic side chain residues of amino acid residues in proteins. In addition, the o-quinone structure can spontaneously react with ECs and form dimers.⁴⁷ Finally, ECs can be involved in the formation of coordination compounds with metal-based scaffolds, which support their bioactive stability and enhance their interactions across applications.⁴⁸

Table 2 provides a summary of the key interactions between ECs and scaffolds in biomedical applications. This includes hydrogen bonding and intercalative binding in scaffolds, which favor binding stability and enhance release properties in anticancer and antibacterial applications.^49–56 Other interactions, such as coordination bonds in metal-based nanoparticles, contribute to the suitability of EC-loaded scaffolds for skin therapy and simulated gastric conditions.^57–59 Together, these interactions highlight the versatility of ECs in the formation of stable complexes across applications, making them promising components in advanced scaffold designs for tissue engineering and regenerative medicine.^33,60–64

Table 2.

Types of Epicatechin Interactions with Various Scaffolds and Their Applications in Biomedical Fields

Interaction	Application	Scaffold type	Ref
Intercalative binding	Anticancer activity	pH-responsive DNA tetrahedron with MUC1-TD to coload CPT-11 and EC	⁵³
Hydrogen bonds	Antibacterial activity	Chitosan membranes containing plant extracts.	⁴⁹
Hydrogen bonds	Antibacterial activity	Chitosan nanoparticles with propolis extracted.	⁵⁰
Coordinate bond	Antibacterial activity	Silver nanoparticles loaded with Ducrosia flabellifolia Boiss extract.	³³
Hydrogen bonds	Simulated gastric	Membrane of sodium alginate with gelatin or chitosan loaded with phenolic compound.	⁵¹
Hydrogen bonds	Anticancer activity	Liposomes loaded with polyphenol-rich grape pomace extracts.	⁵²
Hydrogen bonds	Anticancer activity	Nanoencapsulation of polyphenol in starch nanoparticles	⁵⁴
Hydrogen bonds	Skin therapy	ZnO nanocrystals/Ag nanoparticles loaded with Ximenia americana L.	⁶⁴
Hydrogen bonds	Anticancer activity	Hybrid inulin-soy protein nanoparticle loaded with EC	⁵⁶
Coordination bonds	Skin therapy	Gold nanoparticles are loaded with Aspalathus linearis.	⁵⁷
Intermolecular interactions through pi stacking	Anticancer activity	Polyethylene glycol-boronic acid (PEG-Br) load with EC	⁵⁵
Hydrogen bonds and electrostatic forces	Simulated gastric	Gliadin-gum Arabic nanocarriers loaded with grape pomace.	⁶⁰
Hydrogen bonds	Simulated gastric	Pectin-Zn-alginate gel particles loaded with grape seed extract.	⁶¹
Coordination bonds	Skin therapy	Gold nanoparticles loaded with kiwi peels	⁵⁸
Coordination bonds	Skin therapy	Patches of metal alginates loaded with polyphenol	⁵⁹
Hydrogen bonds	Skin therapy	Silver and gold nanoparticles loaded with polyphenol	⁶²
Coordination bonds	Antibacterial activity	Silver nanoparticles loaded with grape seed extract.	⁶³

Biological Activities Underlying the Mechanism of ECs

ECs offer several significant benefits as bioactive components in biomedical applications because of their broad spectrum of physiological effects and molecular mechanisms.

Anticancer activity

The ability of flavonoids to inhibit the phosphoinositide 3-kinase (PI3K)/Protein kinase B (PkB) (AKT)/Mammalian target of rapamycin pathway makes them promising compounds for cancer prevention and treatment.³⁴ ECs, as extract compounds, have been shown to inhibit the activation of PI3K (in a dose-dependent manner), which is the upstream activator of the AKT pathway. By inhibiting PI3K, ECs, in combination with other bioactive compounds, reduce downstream signaling through AKT, leading to decreased growth and proliferation in cancer cells. This inhibition can induce apoptosis (programmed cell death) and prevent tumor progression (Fig. 2A).^65–68

FIG. 2.

(A) Anticancer activity via the inhibition of PI3K and reduced downstream signaling through AKT-induced apoptosis in cancer cells. (B) Antibacterial activity of ECs disrupted by the lipid bilayer. (C) The antidiabetic activity of ECs promoted the translocation of GLUT4. (D) Antioxidant activity of Keap1 and the release of Nuclear factor erythroid 2-related factor (Nrf2). (E) Anti-inflammatory ECs inhibited NF-kB phosphorylation. PI3K, phosphoinositide 3-kinase.

Antibacterial activity

ECs exert their antibacterial effects through multiple mechanisms, including disrupting bacterial membranes, inducing oxidative stress, inhibiting key bacterial enzymes, disrupting biofilms, and interfering with quorum sensing.

EC antibacterial effects have been demonstrated against a variety of bacteria, including both gram-positive bacteria (such as Staphylococcus aureus and Bacillus subtilis) and gram-negative bacteria (such as Escherichia coli). However, gram-positive bacteria tend to be more susceptible due to the simpler structure of their cell membrane than the more complex outer membrane of gram-negative bacteria.^69,70

Zhang et al.⁷¹ findings indicate that polyphenols may directly interact with cell membranes, causing depolarization and permeabilization, which affect intracellular enzyme activities and ultimately lead to cell apoptosis and bacterial death (Fig. 2B). The antibacterial activity of ECs as stock solutions was evaluated and compared with that of EGCG and CAT. The antimicrobial activity is enhanced by a greater number of hydroxy groups and gallic acid esters; for that reason, EGCG has the highest antimicrobial activity.³¹

Antidiabetic activity

ECs also support improvements in lipid profiles, reduce triglyceride levels, regulate insulin signaling and promote the balance of cholesterol, which is important in preventing complications associated with diabetes.^34,72 ECs have been shown to activate Adenosin Mono Phsophate-activated protein kinase (AMPK) through upstream kinases such as Liver kinase B1 (LKB1) and Calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ), and ECs promote the translocation of GLUT4 (a glucose transporter type 4) to the cell membrane (Fig. 2C). This facilitates the uptake of glucose from the bloodstream into cells, lowering blood sugar levels and improving insulin sensitivity.^73–76

Antioxidant activity

ECs directly scavenge reactive oxygen species (ROS), reducing oxidative stress, a key factor in chronic diseases such as cardiovascular disorders, diabetes, cancer, and neurodegenerative conditions.^77–79 ECs act as mild oxidative stress inducers, leading to the modification of Keap1 and the release of Nrf2. Once Nrf2 is released, it translocates to the nucleus and activates antioxidant genes, providing protection against oxidative stress and cellular damage (Fig. 2D).⁷⁸

Recently, studies on non mammals other than yellow river carp have been conducted. The fish were supplemented with different concentrations of ECs, and the study revealed that muscle antioxidant capacity improved with a dietary concentration of 1000 mg/kg ECs.²⁶ In addition, the antioxidant activity of ECs derived from Smilax glabra extract, along with other flavonoids such as astilbin or neoastilbin, was evaluated via DPPH and ABTS⁺ radical scavenging assays. The results revealed that, among the tested compounds, ECs presented the highest antioxidant activity.⁸⁰

Anti-inflammatory activity of ECs

The antioxidant properties of ECs are attributed to their structure, specifically the presence of phenolic hydroxyl groups that effectively scavenge ROS.⁸¹ Through conjugation and O-methylation, ECs can produce metabolites capable of regulating human vascular function, reducing oxidative damage, and enhancing the ability of ECs to traverse cell membranes.^34,35

The human body is composed of cells that develop a series of processes that can be affected by external factors and produce physiological conditions in which there is an excess of ROS or free radicals. This pathological process is called oxidative stress.^82,83

Oxidative stress is one of the major causes of inflammation, myocardial infarction, and age-related diseases in the long term.⁸⁴ The accumulation of ROS activates nuclear factors such as Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces nitric oxide synthase (iNOS), such as NOX1 and NOX4.⁸³ Treatment with ECs inhibited NF-κB phosphorylation, reducing NO production.⁸⁵ Similarly, studies on the modulation of NOX1 and NOX4 protein release in rats fed high-fat and high-fructose diets revealed that ECs prevented the increase in NOX4;^23–25 however, Prince et al.²⁵ did not affect NOX1 levels (Fig. 2E). In addition, ECs were found to inhibit NO production with an IC₅₀ of 29.08 µM, comparable to that of CAT, which has an IC₅₀ of 30.26 µM. Both flavanols are present in Tilia amurensis extract.⁸⁶ Notably, ECs appear to be more effective at inhibiting NO production than acting as COX-2 transcription suppressors, which is another mechanism underlying their anti-inflammatory effects. This efficacy may be attributed to structural differences, as ECs, such as CAT and EGCG, lack an oxygen group at the C4 position, whereas quercetin, which is considered a potent COX-2 transcription suppressor, has this structural feature.⁸⁷

EC in Regenerative Medicine: Applications and Challenges

ECs are susceptible to oxidation, light, high-temperature and alkaline conditions. In addition to the outstanding benefits of ECs, such as their antioxidant and anti-inflammatory activities, several studies have addressed the ability to develop different constructs of ECs, such as nanoparticles, hydrogels, and electrospun nanofibers (Fig. 3).^5,54,88

FIG. 3.

Schematic representation of the preparation methods of the epicatechin-based scaffolds.

Encapsulation has been employed to increase bioavailability, protect against degradation, and maintain the functional activity of polyphenols.^19,89,90 In addition, hydrogels are perfect candidates for carrying ECs via encapsulation or mixing.⁹¹ Hydrogels are cross-linked hydrophilic polymers that disperse water and are the main constituents of hydrogels; additionally, their properties as shelter proteins and cells allow them to be used as scaffolds.^92,93 Bioactive molecules such as ECs can be incorporated into nanofibers, increasing the bioactive compound loading capacity.^94,95

Cancers

The potential clinical applications of EC in the treatment of drug-resistant cancers are promising because its multiple mechanisms of action can enhance the efficacy of chemotherapy and counteract resistance.⁹⁶ ECs can synergize with chemotherapeutic agents such as a DNA tetrahedron with the MUC1 aptamer to coload irinotecan hydrochloride, which targets cancer cells in acidic environments. This combination enhances drug cytotoxicity in cancer cells, partly by targeting the mitochondria and nucleus, inhibiting extracellular regulated protein kinase (ERK) and reducing oxidative stress, which protects normal cells from damage.⁵³

EC-loaded nanoparticles have shown potential for improving bioavailability and anticancer efficacy, particularly through controlled release systems such as hybrid inulin-soy protein and boronated polyethylene glycol nanocarriers, which facilitate targeted delivery and improve the stability and solubility of ECs in systemic circulation.^55,56

Furthermore, liposome encapsulation in ECs enhances their ability to cross biological barriers and ensures sustained release of the compound at the tumor site, prolonging its anticancer effects. ECs contribute to reducing cancer cell viability primarily through their ability to act as potent antioxidants. Elevated ROS levels in cancer cells are typically linked to oxidative stress, DNA damage, and cell survival pathways that promote tumor growth. By reducing ROS, ECs disrupt these processes, leading to increased apoptosis of cancer cells.^52,97

Bioaccessibility

Bioavailability encompasses bioaccessibility and bioactivity, involving the digestion, absorption, metabolism, and physiological response of the human body to active substances. Studies have explored various encapsulation methods for enhancing the bioavailability of ECs, given their low water solubility and stability in the gastrointestinal tract.⁹⁸

Günter et al.⁶¹ explored pectin-Zn-alginate gel particles loaded with grape seed extract, aiming for controlled release, especially under conditions simulating inflammatory bowel disease. While this system effectively protects ECs through digestion, its bioavailability is still limited by its structural complexity and low absorption rates. In contrast, Carpentieri et al.⁶⁰ utilized a gliadin-gum Arabic nanocarrier system, achieving much greater bioaccessibility, with up to 95.6% of ECs released during digestion. Compared with those of pectin alginate, the nanoscale size and properties of gliadin-containing Arabic promoted better digestion and absorption.

Martinovic et al.⁵¹ further investigated bioaccessibility by encapsulating phenolic compounds from grape pomace in sodium alginate, gelatin, and chitosan systems. These results align with those of Carpentieri et al.⁶⁰ These findings demonstrate that chitosan-based systems increase the release and bioaccessibility of ECs. This highlights that innovating nanocarriers such as chitosan and gum Arabic, which improve the interaction with digestive enzymes and enhance stability, are essential for optimizing the bioavailability of phenolic compounds in supplements.

Skin healing

ECs play a significant role in skin therapy, particularly in tissue regeneration and wound healing applications, because of their potent antioxidant, anti-inflammatory, and antimicrobial properties. ECs incorporated into alginate-based systems were found to maintain their antioxidant activity and support protection of the skin from oxidative damage, making them valuable components in skin patches for wound healing and dermal applications.^3,59,99

Within this framework, Carneiro et al.⁶⁴ developed ZnO nanocrystal/Ag nanoparticles with an extract of Ximenia americana that contained 3.88 g/kg CAT and 1.18 g/kg EC. The results showed that this material contributed positively to skin resistance and had a lower number of mononuclear and polymorphonuclear cells, indicating a reduction in the inflammatory process. In addition, this material promoted greater collagen deposition, which increased the tensile strength of the skin and improved the response to reparation.

Moreover, the inclusion of ECs in bimetallic nanoparticle formulations (such as Au@AgNPs) not only enhances wound closure but also minimizes local irritation, ensuring safer application for skin therapies.⁹⁹ The therapeutic potential of EC-rich extracts in the development of Nanoparticles (NPs) for skin applications has also been explored. Chitosan NPs with propolis extract, which are rich in flavonoids, including ECs, demonstrate strong antimicrobial and antioxidant properties, making them ideal for wound healing and skin repair applications.⁵⁰

Kiwi peel waste and Aspalathus linearis, both of which are rich in polyphenols such as ECs, were loaded in gold NPs. These NPs exhibited potent antioxidant and antibacterial properties, lightened the skin and promoted melanin production.^57,58

Diabetes

A decrease in insulin uptake, attributed to resistance to insulin receptors and pancreatic β-cell dysfunction, leads to glucose accumulation in the bloodstream, a condition known as type II diabetes.^65,100 An oral test involving green tea and chocolate consumption was used to investigate the impact of EC on insulin sensitivity. These findings revealed reduced insulin resistance and blood pressure.⁶⁵

Recently, several studies have focused on the inhibition of digestive enzymes such as α-amylase and α-glucosidase to treat type 2 diabetes. Digestive enzymes degrade carbohydrates into simple sugars.⁷²

The bioactivity against mammalian α-glucosidase tested with EC was positive.¹⁰¹ Furthermore, Xiang et al. compared the inhibitory effects of EGCG, CAT, and EC on the activities of α-amylase and α-glucosidase. EGCG more strongly inhibited α-glucosidase than did the other agents tested because of the presence of a galloyl group, which has a stronger binding affinity for proteins. However, the polymerization of ECs enhanced this inhibitory effect.

Furthermore, another study by Yu et al.¹⁰² showed that a high concentration of polyphenol extract has better inhibitory effects on α-glucosidase in apples. The polyphenol composition of apples is high, especially for procyanidins and ECs.

The hydroxyl groups in EC play an important role in inhibiting enzymes.¹⁰³ Nakhate et al.¹⁰⁴ completed a hydrogel with Acacia catechu Wild that contains ECs in 7.81%, and the hydrogel was used in injured mice with and without diabetes. In addition, Acacia catechu Wild was administered orally. The group treated topically or orally with the extract presented the greatest decrease in blood glucose levels. Furthermore, treatment significantly decreased the expression of IL-1β, IL-6, and Tumor necrosis factor-alpha (TNF-α).

Neurodegenerative disease

In neuroscience, the intricate landscape of neurodegenerative diseases poses a formidable challenge to researchers and clinicians alike. Among these diseases, Parkinson’s disease is a striking example of a disorder with a multifactorial etiology, contributing to its intricate pathophysiology and diverse clinical manifestations.¹⁰⁵ Concurrently, Alzheimer’s disease, the leading cause of dementia, progresses to a neurodegenerative phenomenon characterized by insidious mental memory loss and cognitive decline.¹⁰⁶

Collective evidence from various studies underscores the promising therapeutic potential of ECs across neurodegenerative disorders. Parekh et al.¹⁰⁵ studied nutriosomes containing grape extract and demonstrated the ability of ECs to protect against oxidative damage in Caco-2 cells and mitigate the density of TH-positive cells in a mouse model of Parkinson’s disease. Peng et al.¹⁰⁷ focused on retinal health under sodium iodate-induced stress and revealed the capacity of ECs to enhance mitochondrial structure, ameliorate retinal morphology degeneration, and preserve visual function.

In addition, Ayuda et al.¹⁰⁸ explored the use of ECs in transgenic Caenorhabditis elegans strains expressing human Aβ1-42 peptides and highlighted their neuroprotective effects, reducing β-amyloid accumulation and influencing inflammation and stress-associated genes. Moreover, Gurung et al.¹⁰⁹ reported the beneficial effects of E. alatus twig extract, which is rich in flavonoids, including ECs, on cognitive deficits through the restoration of cholinergic systems and the Brain-derived neurotrophic factor/ERK/cyclic AMP response element-binding protein pathway. Although certain limitations are presented, Qureshi et al.¹¹⁰ evaluated the efficacy of ECs in pediatric subjects with Friedreich ataxia, and the results did not reveal statistically significant improvements in primary neurological outcomes; however, improvements in cardiac structure and function were observed.

Bone tissue engineering

Bones have been studied as part of tissue engineering, and owing to the characteristics of ECs, several studies have shown improvements in bone repair and regeneration.¹¹¹

Osteoarthritis (OA), a disease that affects bones, is characterized by increased TNF-α and nitric oxide levels that cause inflammation. In an attempt to discern the influence of ECs on this disease, Osman, Wan et al.¹¹² reported a decrease in glycosaminoglycan and nitric oxide in fresh bovine cartilage that did not depend on the dose of ECs. In addition, in male rats with OA, a Morinda citrifolia extract (containing EC) was administered, and apparently, the extract did not affect the level of the bone formation biomarker Procollagen type I N-terminal propeptide, increasing the induction of OA.

In this framework, Imtiyaz, Z et al.¹¹³ studied primary human osteoblasts, and EC increased the levels of mineralization and ALP, a biomarker of bone formation. On the other hand, Martin et al.¹¹⁴ also showed the beneficial effect of ECs on primary cilium length, and ECs reduced the overexpression of these genes in mutant chondrocytes.³⁸

Meta-Analysis of EC-Enhanced Scaffolds and Nanocarriers

This meta-analysis provides a comprehensive evaluation of the role of ECs as bioactive components in tissue engineering scaffolds, synthesizing data from various studies to assess their antibacterial, anticancer, bioaccessibility, and skin healing properties (Supplementary Table S1, Supplementary Figure S1). By pooling the results, the analysis increases the reliability and generalizability of the conclusions, offering valuable insights into the conditions under which ECs are most effective (Supplementary Tables S2, S3, S4, S5 and S6). This study also revealed significant heterogeneity across studies, emphasizing the need for standardized methodologies to clarify the potential of ECs in different applications (Supplementary Tables S7, S8, S9 and S10).¹¹⁵ In highlighting both consistent trends and gaps in the research, this meta-analysis serves as a foundation for future studies aiming to refine the use of ECs in tissue engineering and related fields.

The findings revealed that EC-loaded scaffolds were shown to reduce cancer cell viability, particularly in HepG2 and SH-SY57 cells, suggesting strong anticancer potential (Supplementary Figures S2 and S3). In addition, the antibacterial efficacy of ECs increased with increasing concentration in the scaffolds, though the significant variability between studies highlighted the need for standardized research to better understand the optimal conditions for the antibacterial effects of ECs (Supplementary Figures S4 and S5). In skin healing, ECs have demonstrated promising improvements, although substantial differences in study designs, EC concentrations, and outcome measures have led to high heterogeneity in the findings (Supplementary Figure S6). This inconsistency highlights the need for more rigorous and standardized research protocols to fully understand the role of ECs in skin repair and their broader potential in tissue engineering applications.

The bioaccessibility of ECs across gastrointestinal tests yielded mixed results due to high heterogeneity among studies, with scaffold types and test conditions contributing to the variation (Supplementary Figure S7). Despite some consistency within subgroups, the complexity of EC release dynamics in different gastrointestinal environments calls for more uniform methodologies in future studies to produce clearer, more reliable insights.

Limitations

This study has several limitations that warrant consideration. First, the variability in experimental conditions across the reviewed studies—such as differing scaffold types, concentrations of ECs, and release environments—introduces heterogeneity that complicates direct comparison and synthesis of findings. In addition, the stability and bioavailability challenges associated with ECs, particularly in oxidative or gastrointestinal conditions, limit the translatability of in vitro results to clinical applications. Another limitation is the lack of long-term in vivo studies assessing the efficacy and safety of EC-based scaffolds, particularly in complex tissue environments, which restricts the understanding of potential side effects or degradation pathways in clinical settings. Finally, while this review discusses various encapsulation techniques, standardized methodologies are needed to consistently evaluate EC release dynamics, which are crucial for effective therapeutic applications. Addressing these limitations in future research could enhance the applicability and reliability of ECs in tissue engineering.

In regenerative medicine, in vivo models are crucial for evaluating the stability and effectiveness of ECs. The selection of an appropriate animal model requires researchers to consider its relevance to the research question and clinical objectives. In vitro and ex vivo experiments, along with in silico modeling, can reduce the need for in vivo studies during the early stages of development.¹¹⁶ In addition, advanced delivery systems, such as nanoparticles, can be tested in both in vitro and in vivo models to increase compound stability and effectiveness.¹¹⁷

Concluding Remarks and Outlook

This systematic review and meta-analysis highlight the significant potential of EC derivatives as bioactive components in tissue engineering. ECs exhibit robust antioxidative, anti-inflammatory, antibacterial, and anticancer activities that contribute positively to scaffold-based tissue regeneration approaches. The integration of ECs into diverse scaffold forms—including hydrogels, nanoparticles, and nanofibers—has improved tissue repair outcomes, particularly in bone, skin, and cancer therapies.

However, challenges remain in maximizing the clinical utility of ECs owing to stability and bioavailability limitations, as well as variations in release dynamics across different gastrointestinal and tissue environments. Future research should prioritize the development of standardized methodologies to improve data reliability and comparability, thereby clarifying the optimal conditions for EC scaffold efficacy. In addition, advanced encapsulation and scaffold engineering techniques are essential for overcoming bioavailability barriers, enhancing the bioactivity of ECs, and ensuring targeted, sustained release.

Looking ahead, continued interdisciplinary research on EC–cell interactions and scaffold technology promises to drive further advancements in regenerative medicine. EC-based materials are well positioned to play a foundational role in next-generation biomedical applications, offering promising pathways to more effective and bioactive therapeutic scaffolds.

Authors’ Contributions

E.M., G.H.G.G., A.M.C., and M.G.T.: Conceptualization, article preparation, edits, proofreading, preparation of figures, and formatting. E.M. and M.G.T.: Conceptualization, edits, proofreading, and formatting.

Footnotes

Acknowledgments

E.M. thanks CONAHCyT-México. This work was supported by the UNAM Postdoctoral Program (POSDOC).

Funding Information

This review is supported by projects CF-2023-I-1759, I × M 376, and INRLGII 73/22 PA, which are led by M.G.T. from the Biotechnology Laboratory at the National Rehabilitation Luis Guillermo Ibarra Ibarra Institute & CONAHCyT.

Disclaimer

M.G.T., A.M.C., and G.H.G.G. are members of the Sistema Nacional de Investigadores, CONAHCyT, México.

Disclosure Statement

All the authors have read the article and declare that they have no conflicts of interest. No writing assistance was utilized in the production of this article.

Supplemental Material

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