Retinal degenerative diseases, primarily owing to the gradual loss of neuronal cells, could lead to blindness. Transplantation of retinal progenitor cells (RPCs), which had the unique ability to differentiate into neuronal cells, offered promising therapeutic potential for these diseases. However, a critical challenge in stem cell therapy was the efficient promotion of the directed proliferation and differentiation of progenitor cells. To overcome this limitation, we formulated a zinc silicate bioceramic (ZS) composite hydrogel. The experimental outcomes demonstrated that this novel material possessed substantial advantages and immense possibilities for mimicking the extracellular matrix environment, thereby effectively modulating stem cell proliferation and differentiation. Notably, it enhanced the differentiation of RPCs into neurons while suppressing glial cell differentiation. In particular, ZS had an exceptional capacity to induce the differentiation of RPCs into photoreceptor cells, a specialized type of neuronal cell. It was important to highlight that the ZS composite hydrogel predominantly facilitated the differentiation of RPCs through activation of the Tiam2-Rac signaling pathway. Concurrently, it stimulated proliferation via activation of the AKT and ERK signaling pathways. The Zn ions in the ZS composite hydrogel primarily promoted the proliferation of RPCs, while the synergistic effect of Zn ions and Si ions contributed to reducing inflammatory factor expression and promoting the neuronal differentiation of RPCs. In conclusion, the meticulous modulation of RPC proliferation and differentiation mediated by ZS bioceramics held promise for novel therapeutic strategies of retinal degenerative diseases and neurodegenerative disorders.

Addressing the concurrent repair of cartilage and subchondral bone presents a significant challenge yet is crucial for the effective treatment of severe joint injuries. This study introduces a novel biodegradable composite scaffold, integrating piezoelectric poly-L-lactic acid (pPLLA) with strontium-enriched silicate bioceramic (SrSiO3). This innovative scaffold continually releases bioactive Sr2+ and SiO32- ions while generating an electrical charge under low-intensity pulsed ultrasound (LIPUS) stimulation, a clinically recognized method. The scaffold's unique dual action, emanating both chemical and electrical signals, activates the purinergic receptor P2X 1 (P2RX1) calcium ion channel, promoting an influx of intracellular calcium ions. This process results in a synergistic enhancement of both chondrogenic activities of rat chondrocytes (rCCs) and osteogenic activities of rat bone marrow mesenchymal stem cells (rBMSCs). Furthermore, the scaffold's effectiveness in integrating articular cartilage and subchondral bone repair is confirmed in a rat model of joint osteochondral injury. This study thereby offers a groundbreaking approach for treating severe osteoarticular cartilage defects.

Inspired by the scar-free wound healing in infants, an anti-scar strategy is proposed by accelerating wound healing using silicate bioactive materials. Bioglass/alginate composite hydrogels are applied, which significantly inhibit scar formation in rabbit ear scar models. The underlining mechanisms include stimulation of Integrin Subunit Alpha 2 expression in dermal fibroblasts to accelerate wound healing, and induction of apoptosis of hypertrophic scar fibroblasts by directly stimulating the N-Acylsphingosine Amidohydrolase 2 expression in hypertrophic scar fibroblasts, and indirectly upregulating the secretion of Cathepsin K in dermal fibroblasts. Considering specific functions of the bioactive silicate materials, two scar treatment regimes are tested. For severe scars, a regenerative intervention is applied by surgical removal of the scar followed by the treatment with bioactive hydrogels to reduce the formation of scars by activating dermal fibroblasts. For mild scars, the bioactive dressing is applied on the formed scar and reduces scar by inducing scar fibroblasts apoptosis.

Peri-implant lesion is a grave condition afflicting numerous indi-viduals with dental implants. It results from persistent periodontal bacteria accumulation causing inflammation around the implant site, which can primarily lead to implant loosening and ultimately the implant loss. Early-stage peri-implant lesions exhibit symptoms akin to gum disease, including swelling, redness and bleeding of the gums surrounding the implant. These signs indicate infection and inflammation of the peri-implant tissues, which may result in bone loss and implant failure. To address this problem, a thermionic strategy was applied by designing a cuprorivaite-hardystonite bioceramic/alginate composite hydrogel with photothermal and Cu/Zn/Si multiple ions releasing property. This innovative approach creates a thermionic effect by the release of bioactive ions (Cu2+ and Zn2+ and SiO32-) from the composite hydrogel and the mild heat environment though the photothermal effect of the composite hydrogel induced by near-infrared light irradiation. The most distinctive advantage of this thermionic effect is to substantially eliminate periodontal pathogenic bacteria and inhibit inflammation, while simultaneously enhance peri-implant osseointegration. This unique attribute renders the use of this composite hydrogel highly effective in significantly improving the survival rate of implants after intervention in peri-implant lesions, which is a clinical challenge in periodontics. This study reveals application potential of a new biomaterial-based approach for peri-implant lesion, as it not only eliminates the infection and inflammation, but also enhances the osteointegration of the dental implant, which provides theoretical insights and practical guidance to prevent and manage early-stage peri-implant lesion using bioactive functional materials.

Regenerating skin nerves in deep burn wounds poses a significant clinical challenge. In this study, we designed an electrospun wound dressing called CuCS/Cur, which incorporates copper-doped calcium silicate (CuCS) and curcumin (Cur). The unique wound dressing releases a bioactive Cu2+-Cur chelate that plays a crucial role in addressing this challenge. By rebuilding the "factory" (hair follicle) responsible for producing nerve cells, CuCS/Cur induces a high expression of nerve-related factors within the hair follicle cells and promotes an abundant source of nerves for burn wounds. Moreover, the Cu2+-Cur chelate activates the differentiation of nerve cells into a mature nerve cell network, thereby efficiently promoting the reconstruction of the neural network in burn wounds. Additionally, the Cu2+-Cur chelate significantly stimulates angiogenesis in the burn area, ensuring ample nutrients for burn wound repair, hair follicle regeneration, and nerve regeneration. This study confirms the crucial role of chelation synergy between bioactive ions and flavonoids in promoting the regeneration of neuralized skin through wound dressings, providing valuable insights for the development of new biomaterials aimed at enhancing neural repair.

ExplorationVolume 4, Issue 3 20240302 BACK COVEROpen Access Back Cover: Ion cocktail therapy for myocardial infarction by synergistic regulation of both structural and electrical remodeling (EXP2 3/2024) Yumei Que, Yumei QueSearch for more papers by this authorJiaxin Shi, Jiaxin ShiSearch for more papers by this authorZhaowenbin Zhang, Zhaowenbin ZhangSearch for more papers by this authorLu Sun, Lu SunSearch for more papers by this authorHairu Li, Hairu LiSearch for more papers by this authorXionghai Qin, Xionghai QinSearch for more papers by this authorZhen Zeng, Zhen ZengSearch for more papers by this authorXiao Yang, Xiao YangSearch for more papers by this authorYanxin Chen, Yanxin ChenSearch for more papers by this authorChong Liu, Chong LiuSearch for more papers by this authorChang Liu, Chang LiuSearch for more papers by this authorShijie Sun, Shijie SunSearch for more papers by this authorQishu Jin, Qishu JinSearch for more papers by this authorYanxin Zhang, Yanxin ZhangSearch for more papers by this authorXin Li, Xin LiSearch for more papers by this authorMing Lei, Ming LeiSearch for more papers by this authorChen Yang, Chen YangSearch for more papers by this authorHai Tian, Hai TianSearch for more papers by this authorJiawei Tian, Jiawei TianSearch for more papers by this authorJiang Chang, Jiang ChangSearch for more papers by this author Yumei Que, Yumei QueSearch for more papers by this authorJiaxin Shi, Jiaxin ShiSearch for more papers by this authorZhaowenbin Zhang, Zhaowenbin ZhangSearch for more papers by this authorLu Sun, Lu SunSearch for more papers by this authorHairu Li, Hairu LiSearch for more papers by this authorXionghai Qin, Xionghai QinSearch for more papers by this authorZhen Zeng, Zhen ZengSearch for more papers by this authorXiao Yang, Xiao YangSearch for more papers by this authorYanxin Chen, Yanxin ChenSearch for more papers by this authorChong Liu, Chong LiuSearch for more papers by this authorChang Liu, Chang LiuSearch for more papers by this authorShijie Sun, Shijie SunSearch for more papers by this authorQishu Jin, Qishu JinSearch for more papers by this authorYanxin Zhang, Yanxin ZhangSearch for more papers by this authorXin Li, Xin LiSearch for more papers by this authorMing Lei, Ming LeiSearch for more papers by this authorChen Yang, Chen YangSearch for more papers by this authorHai Tian, Hai TianSearch for more papers by this authorJiawei Tian, Jiawei TianSearch for more papers by this authorJiang Chang, Jiang ChangSearch for more papers by this author First published: 18 June 2024 https://doi.org/10.1002/EXP.20240302AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Ion cocktail consisting of silicate, strontium and copper ions significantly reduces the deteriorative electrical and structural remodeling after myocardial infarction by stimulating angiogenesis of endothelial cells and M2 polarization of macrophages, and inhibiting cardiomyocyte apoptosis under hypoxia/ischemic condition. This ion cocktail therapy reveals a new strategy to effectively treat myocardial infarction with clinical translation potential. Volume4, Issue3June 202420240302 RelatedInformation

In light of the clinical challenges posed by bacterial infection and vascular damage in chronic diabetic wounds, this study presents a novel bioactive copper vanadate-based hydrogel (CVH) with multiple functions including the sustained release of copper and vanadium ions, photocatalytic activity under visible (VIS) light, and photothermal ability under near-infrared (NIR) light. In vitro experiments demonstrated that CVH effectively repairs high glucose-impaired human umbilical vein endothelial cells (HUVECs) and exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Furthermore, the dual biological functions are augmented by the NIR-light-induced mild photothermal effect, demonstrating a synergistic effect. The infected diabetic wound model further substantiates the therapeutic efficacy of the CVH dressing in eliminating bacteria and promoting angiogenesis under VIS/NIR light irradiation. Collectively, the CVH dressing demonstrates significant potential as a therapeutic intervention for managing chronic diabetic wounds.

Oral submucous fibrosis (OSF) is a chronic, inflammatory and potentially malignant oral disorder. Its pathophysiology is extremely complex, including excessive collagen deposition, massive inflammatory infiltration, and capillary atrophy. However, the existing clinical treatment methods do not fully take into account all the pathophysiological processes of OSF, so they are generally low effective and have many side effects. In the present study, we developed an injectable sodium hyaluronate/45S5 bioglass composite hydrogel (BG/HA), which significantly relieved mucosal pallor and restricted mouth opening in OSF rats without any obvious side effects. The core mechanism of BG/HA in the treatment of OSF is the release of biologically active silicate ions, which inhibit collagen deposition and inflammation, and promote angiogenesis and epithelial regeneration. Most interestingly, silicate ions can overall regulate the physiological environment of OSF by down-regulating alpha-smooth muscle actin ( alpha-SMA) and CD68 and up-regulating CD31 expression, as well as regulating the expression of pro-fibrotic factors [transforming growth factor- beta 1 ( TGF- beta 1 ), interleukin-10 ( IL-10 ), tumor necrosis factor- alpha ( TNF- alpha) and tissue inhibitors of metalloproteinase-1 ( TIMP-1 )] and anti-fibrotic factors [interleukin-1 beta ( IL-1 beta)] in macrophage. In conclusion, our study shows that BG/HA has great potential in the clinical treatment of OSF, which provides an important theoretical basis for the subsequent development of new anti-fibrotic clinical preparations.

Traditional wound dressings lack the activity to promote hair follicle regeneration during the treatment of deep burn skin injuries. In this study, a composite electrospun wound dressing (SZS + PG) containing strontium zinc silicon bioceramics (Sr2ZnSi2O7, SZS) was designed, which efficiently released bioactive Sr2+, Zn2+ and SiO32- ions. Owing to the synergistic effect of these three ions, SZS + PG not only significantly activated hair follicle stem cells around the burn wound, but also significantly promoted the regeneration of capillaries in the damaged area, thereby effectively promoting the hair follicle regeneration in burn wounds. This study confirmed that the combination of different functional ions is an effective way to facilitate burn wound healing with high qualitative hair follicle regeneration, which provided a new consideration for the development of novel wound dressings for burn wound treatment.

Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an "ion cocktail therapy" is proposed to simultaneously reverse cardiac structural and electrical remodeling post-MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post-MI by ameliorating infarct size, promoting angiogenesis in both peri-infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination.

Chronic pancreatitis (CP) is a multifactorial fibroinflammatory syndrome. At present, there is no effective way to treat it clinically. In this study, we proposed a new approach by application of a highly active calcium silicate ion solution derived from calcium silicate (CS) bioceramics, which effectively inhibited the development of CP. This bioceramic derived bioactive ionic solution mainly regulated pancreatic acinar cells (PACs), macrophages and pancreatic stellate cells (PSCs) by SiO32- ions to inhibit inflammation and fibrosis and promote acinar regeneration. The possible mechanism of the therapeutic effect of CS ion solution mainly includes the inhibition of PAC apoptosis by down-regulating the c-caspase3 signal pathway and promotion of the regeneration of PACs by up-regulating the WNT/β-catenin signaling pathway. In addition, the CS ion solution also effectively down-regulated the NF-κB signaling pathway to reduce macrophage infiltration and PAC inflammatory factor secretion, thereby reducing PSC mediated pancreatic fibrosis. This bioceramics-based ion solution provides a new idea for disease treatment using biomaterials, which may have the potential for the development of new therapy for CP.

The regeneration of hair follicles lost from injury or disease represents a major challenge in cutaneous regenerative medicine. In this study, we investigated the synergetic effects between zinc and silicon ions on dermal cells and screened the optimal concentration of ions for medical applications. We integrated zinc/silicon dual ions into gelatin methacryloyl (GelMA) to bioprint a scaffold and determined that its mechanical properties are suitable for biological treatment. Then, the scaffold was employed to treat mouse excisional model in order to promote in situ hair follicle regeneration. Our findings showed that GelMA-zinc/silicon-printed hydrogel can significantly activate hair follicle stem cells and enhance neovascularization. The beneficial effects of the scaffold were further confirmed by the growth of hairs in the center of wounds and the improvement in perfusion recovery. Taken together, the present study is the first to combine GelMA with zinc/silicon dual ions to bioprint in situ for treating excisional wound, and this approach may regulate hair follicle regeneration not only directly by impacting stem cells but also indirectly through promoting angiogenesis.

Multiple myeloma (MM) is the second most common hematologic malignancy. Bortezomib (BOR), a first-generation proteasome inhibitor, is the basic agent for the treatment of MM and has greatly improved the survival of patients with MM. However, the side effects of BOR (e.g. peripheral neuropathy) occur frequently and almost all MM patients eventually develop resistance to BOR and go on to develop refractory relapsed multiple myeloma (RRMM). Therefore, it is of great significance to find a method to increase the sensitivity of MM to BOR to reduce toxicity and drug resistance. Herein, we found that calcium silicate (CS), a silicate bioceramic that releases Si ions (SIs), enhanced the BOR anti-myeloma effect in vitro in human myeloma cell lines (HMCLs), including BOR-resistant cell lines (U266/BOR). The enhanced anti-myeloma effect of these two agents was demonstrated in primary MM cells regardless of disease status and in MM xenograft mice. Mechanistically, SI enhanced G2/M cell cycle arrest and the inhibition of the NF-κB pathway induced by BOR. These results imply that the combination of SI and BOR (SI/BOR) is a promising way to overcome BOR resistance in MM and RRMM. The future use of nanotechnology to prepare CS nanomaterials as BOR carriers for the treatment of MM and RRMM is a very promising clinical application.

Aortic aneurysm and dissection (AAD) are leading causes of death in the elderly. Recent studies have demonstrated that silicate ions can manipulate multiple cells, especially vascular-related cells. We demonstrated in this study that silicate ions as soluble form of bioactive ceramics effectively alleviated aortic aneurysm and dissection in both Ang II and β-BAPN induced AAD models. Different from the single targeting therapeutic drug approaches, the bioactive ceramic derived approach attributes to the effect of bioactive silicate ions on the inhibition of the AAD progression through regulating the local vascular microenvironment of aorta systematically in a multi-functional way. The in vitro experiments revealed that silicate ions did not only alleviate senescence and inflammation of the mouse aortic endothelial cells, enhance M2 polarization of mouse bone marrow-derived macrophages, and reduce apoptosis of mouse aortic smooth muscle cells, but also regulate their interactions. The in vivo studies further confirm that silicate ions could effectively alleviate senescence, inflammation, and cell apoptosis of aortas, accomplished with reduced aortic dilation, collagen deposition, and elastin laminae degradation. This bioactive ceramic derived therapy provides a potential new treatment strategy in attenuating AAD progression.

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr2+ and SiO32- ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

Significant progress has been made in the design of smart fibers toward achieving improved efficacy in tissue regeneration. While electrospun fibers can be engineered with shape memory capability, both the fiber structure and applied shape-programming parameters are the determinants of final performance in applications. Herein, we report a comparison study on the shape memory responses compared between electrospun random and aligned fibers by varying the programming temperature T prog and the deforming strain ε deform . A PLLA–PHBV (6:4 mass ratio) polymer blend was first electrospun into random and aligned fibrous mat forms; thereafter, the effects of applying specific T prog (37°C and 46°C) and ε deform (30%, 50%, and 100%) on the morphological change, shape recovery efficiency, and switching temperature T sw of the two types of fibrous structures were examined under stress-free condition, while the maximum recovery stress σ max was determined under constrained recovery condition. It was identified that the applied T prog had less impact on fiber morphology, but increasing ε deform gave rise to attenuation in fiber diameters and bettering in fiber orientation, especially for random fibers. The efficiency of shape recovery was found to correlate with both the applied T prog and ε deform , with the aligned fibers exhibiting relatively higher recovery ability than the random counterpart. Moreover, T sw was found to be close to T prog , thereby revealing a temperature memory effect in the PLLA–PHBV fibers, with the aligned fibers showing more proximity, while the σ max generated was ε deform -dependent and 2.1–3.4 folds stronger for the aligned one in comparison with the random counterpart. Overall, the aligned fibers generally demonstrated better shape memory properties, which can be attributed to the macroscopic structural orderliness and increased molecular orientation and crystallinity imparted during the shape-programming process. Finally, the feasibility of using the shape memory effect to enable a mechanoactive fibrous substrate for regulating osteogenic differentiation of stem cells was demonstrated with the use of aligned fibers.

In clinical practice, it has become urgent to develop multifunctional wound dressings that can combat infection and prompt wound healing simultaneously. In this study, we proposed a polydopamine/alginate/nanoselenium composite hydrogel (Alg-PDA-Se) for the treatment of infected wounds. In particular, polydopamine endows the composite hydrogel with controllable near-infrared photothermal properties, while low-dosage selenium nanoparticles (Se NPs) offer excellent anti-oxidation, anti-inflammatory, pro-proliferative, pro-migration, and pro-angiogenic performances, which are verified by multiple cells, including macrophages, fibroblasts, and endothelial cells. More interestingly, the combination of mild temperature with low-dosage Se NPs produces a synergistic effect on combating both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) and promoting the healing of bacteria-infected wounds in vivo. We anticipate that the designed composite hydrogel might be a potential candidate for anti-infection bioactive dressing.

Extracellular vesicles have shown good potential in disease treatments including ischemic injury such as myocardial infarction. However, the efficient production of highly active extracellular vesicles is one of the critical limitations for their clinical applications. Here, we demonstrate a biomaterial-based approach to prepare high amounts of extracellular vesicles with high bioactivity from endothelial progenitor cells (EPCs) by stimulation with silicate ions derived from bioactive silicate ceramics. We further show that hydrogel microspheres containing engineered extracellular vesicles are highly effective in the treatment of myocardial infarction in male mice by significantly enhancing angiogenesis. This therapeutic effect is attributed to significantly enhanced revascularization by the high content of miR-126a-3p and angiogenic factors such as VEGF and SDF-1, CXCR4 and eNOS in engineered extracellular vesicles, which not only activate endothelial cells but also recruit EPCs from the circulatory system.

Nanozymes, emerging nanomaterials for wound healing, exhibit enzyme-like activity to modulate the levels of reactive oxygen species (ROS) at wound sites. Yet, the solo regulation of endogenous ROS by nanozymes often falls short, particularly in chronic refractory wounds with complex and variable pathological microenvironments. In this study, we report the development of a multifunctional wound dressing integrating a conventional alginate (Alg) hydrogel with a newly developed biodegradable copper hydrogen phosphate (CuP) nanozyme, which possesses good near-infrared (NIR) photothermal conversion capabilities, sustained Cu ion release ability, and pH-responsive peroxidase/catalase-mimetic catalytic activity. When examining acute infected wounds characterized by a low pH environment, the engineered Alg/CuP composite hydrogels demonstrated high bacterial eradication efficacy against both planktonic bacteria and biofilms, attributed to the combined action of catalytically generated hydroxyl radicals and the sustained release of Cu ions. In contrast, when applied to chronic diabetic wounds, which typically have a high pH environment, these composite hydrogels exhibit significant angiogenic performance. This is driven by the provision of catalytically generated dissolved oxygen and a beneficial supplement of Cu ions released from the degradable CuP nanozyme. Further, a mild thermal effect induced by NIR irradiation amplifies the catalytic activities and bioactivity of Cu ions, thereby enhancing the healing process of both infected and diabetic wounds. Our study validates that the synergistic integration of photothermal effects, catalytic activity, and released Cu ions can concurrently yield high antibacterial efficiency and tissue regenerative activity, rendering it highly promising for various clinical applications in wound healing.

In the pursuit of therapeutic strategies for myocardial infarction (MI), a pivotal objective lies in the concurrent restoration of blood perfusion and reduction of cardiomyocyte apoptosis. However, achieving these dual goals simultaneously presents a considerable challenge. In this study, a Zn2SiO4 bioceramic capable of concurrently sustaining the release of bioactive SiO32- and Zn2+ ions, which exhibit a synergistic impact on endothelial cell angiogenesis promotion, cardiomyocyte apoptosis inhibition, and myocardial mitochondrial protection against oxygen-free radical (reactive oxygen species) induced injury is developed. Furthermore, in vivo outcomes from a murine MI model demonstrate that either systemic administration via tail vein injection of Zn2SiO4 extract or local application through intramyocardial injection of a Zn2SiO4 composite hydrogel promotes cardiac function and reduces cardiac fibrosis, thus aiding myocardial repair. This research is the first to elucidate the advantageous effects of dual bioactive ions in myocardial protection and may offer a novel therapeutic avenue for ischemic heart disease based on meticulously engineered bioceramics.