Injectable Hydrogel-Based Combination Therapy for Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Trials

doi:10.21203/rs.3.rs-3400144/v1

Download PDF

Research Article

Injectable Hydrogel-Based Combination Therapy for Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Trials

https://doi.org/10.21203/rs.3.rs-3400144/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 21 Feb, 2024

Read the published version in BMC Cardiovascular Disorders →

You are reading this latest preprint version

Introduction:

This study evaluates the efficacy of a combined regimen based on injectable hydrogels for the treatment of experimental myocardial infarction.

Patient concerns:

Myocardial infarction is an acute illness associated with a decline in quality of life and increased mortality. Experimental myocardial infarction models can facilitate disease research for developing therapies that effectively manage disease progression and promote tissue repair.

Diagnosis:

An experimental myocardial infarction animal model was established using the ligation method of the anterior descending branch of the left coronary artery (LAD).

Interventions:

The efficacy of combining hydrogels with various therapies for intramyocardial injection was assessed to evaluate the functional and morphological improvements in the post-infarction heart achieved through the combined hydrogel regimen.

Outcomes:

The literature review spanned PubMed, Web of Science, Scopus, and Cochrane databases. A total of 83 papers were included in the meta-analysis according to the inclusion and exclusion criteria. When analyzing a murine small animal model, the combination therapy group using hydrogel showed a significant improvement in the primary outcome of left ventricular ejection fraction, with an overall effect size of 11.68 (95% confidence interval (CI): 10.24,13.12) compared to the group receiving hydrogel injection alone. The overall effect size for short-axis shortening was 6.25 (95% CI: 5.98,6.52). Subgroup analysis suggested that the source of hydrogel had a minor impact on the treatment outcome.

Conclusion

The present study demonstrated that combining hydrogel with other therapies effectively treated myocardial infarction, improving heart function and morphology. More research and clinical trials should be conducted using large animal models for further study and validation.

Hydrogel

myocardial infarction

Combination Therapy

Myocardial infarction, resulting from sudden myocardial tissue ischemia and cell damage, leads to irreversible cardiac impairment [1]. Following the injury, both acute and chronic inflammation during the recovery phase, coupled with an increased cardiac load due to diminished heart function, exacerbate heart tissue damage. This detrimental cycle of "injury - increased cardiac load - heightened injury" ultimately progresses to heart failure [2]. Despite being a principal cause of global morbidity and mortality [3], treatments for myocardial infarction encompass drug therapy, surgical device implantation, and organ transplantation. Among these, drug therapy is the most accessible, aiming to decelerate cardiac injury progression by lessening the cardiac load. However, its effectiveness is limited, often accompanied by systemic toxicity and suboptimal drug utilization, thus undermining the potential benefits of many clinical agents.

Bioactive scaffolds combined with bioactive drugs or cells, facilitating cellular attachments, have garnered attention for promoting tissue repair following myocardial infarction and reversing heart damage [4]. Current bioactive scaffolds include hydrogels, patches, and nanoparticles [5]. Hydrogels, hydrophilic polymeric three-dimensional networks [6], possess suitable mechanical properties, moisturizing attributes, biocompatibility, biodegradability, and biomimetic characteristics, making them vital for sustained drug delivery and tissue regeneration [7]. Despite their advantages, hydrogels as biomaterials have a relative deficit in bioactivity [8]. However, hydrogels can exhibit anti-inflammatory, anti-apoptotic, and tissue repair capabilities by integrating various bioactive drugs, cells, and cellular appendages. Targeted injections into the myocardial infarction area can ensure the prolonged release of therapeutic agents, stabilizing therapeutic outcomes and enhancing prognosis [9].

Injectable hydrogel combination therapies for myocardial infarction are frequently explored in preclinical studies. The reviewed literature encompasses cellular therapies, cytokine therapies, pharmacotherapies, extracellular vesicular therapies, and nucleic acid therapies. Beyond the aforementioned monotherapy combination hydrogels, multitherapy, involving multiple therapies or diverse combinations within the same therapy, is also considered.

Despite numerous preclinical studies, clinical investigations concerning hydrogel-based treatments for myocardial infarction remain limited [10, 11], predominantly centering on hydrogel combined with stem cell therapies. Drawing from prior systematic review and meta-analysis literature, we delved deeper into hydrogel-based therapeutic approaches [12]. Our analysis examined the effects of combining hydrogel with different therapies on post-myocardial infarction cardiac function and morphology, providing valuable insights for future research and facilitating the clinical application of hydrogel combination therapy.

2.1. Protocols and Registration

This meta-analysis adhered to the Preferred Reporting Items for Systematic Evaluation and Meta-Analysis (PRISMA) guidelines (Supplementary Table I). The review protocol was registered on PROSPERO (CRD42023401702).

2.2. Search Strategy and Data Sources

For this meta-analysis, relevant research literature was sourced from:

PubMed (National Library of Medicine, 2021/03/01).

Web of Science (via Clarivate Analytics).

Scopus (via Elsevier 1788–2021/03/01).

Cochrane Central Register of Controlled Trials (via The Cochrane Library, 2021/03/01)

The search strategy for PubMed is presented in Supplementary Table II.

2.3. Study Eligibility

Two independent evaluators (H.G. and T.Y.) began by assessing literature titles and abstracts against inclusion and exclusion criteria (Supplementary Table Ⅲ). Following this, both evaluators undertook a comprehensive full-text review. This review evaluated the outcomes of using injectable hydrogels combined with various therapies (cellular therapy, pharmacotherapy, cytokine therapy, extracellular vesicular therapy, nucleic acid therapy, and polypharmacy) in animal models of myocardial infarction induced by LAD ligation to assess cardiac functional and morphological improvements post-treatment. To mitigate potential errors from varied study protocols, we mandated that the treatment follow-up duration in the studies exceed one week [12, 13]. The infarct model was clearly defined as an animal model established using left anterior descending branch ligation, ensuring consistent and reliable results. Studies indicating immunogenic reactions or those involving only hydrogel injection without other therapies were excluded. Literature inclusion held no restrictions based on language or publication date.

Primary outcome indicators in the study encompass left ventricular Ejection Fraction and Fractional Shortening. Included literature must present at least one of these primary outcome measures. Secondary outcome indicators feature left ventricular end-systolic volume (ESV), end-diastolic volume (EDV), end-systolic diameter (ESD), end-diastolic diameter (EDD), infarct size, and anterior wall thickness, encompassing both cardiac functional and morphological parameters. In cases where the necessary data were absent in the literature, yet evidence suggested the collection of primary outcome measures, the respective authors were approached via e-mail. They were given two weeks from the date of the e-mail to provide the required information.

2.4. Data Extraction

The relevant data in this analysis were extracted using a standardized approach, including experimental animal sample size, Ejection Fraction (baseline, hydrogel, and combined protocol groups), Fractional Shortening (baseline, hydrogel alone, and combined protocol groups), LV End-Systolic Diameter (hydrogel alone, combined protocol groups), LV End-Diastolic Diameter (hydrogel alone, combined protocol groups), LV End-Systolic Volume (hydrogel alone, combined protocol groups), LV End-Diastolic Volume (hydrogel alone, combined protocol groups), Infarct area (hydrogel alone, combined protocol groups), and anterior ventricular wall thickness (hydrogel alone, combined protocol groups). Manual extraction was performed using Image J software when data appeared exclusively in graphical format. To ensure data precision, SS.Q and JL.Y simultaneously conducted the extraction. Any discrepancies in extraction outcomes prompted a separate re-measurement to maintain data accuracy.

Literature data were extracted in the format of mean and standard deviation. When the mean standard deviation was not provided, conversion was undertaken using standard errors and confidence intervals, in line with the Cochrane Collaboration Network guidelines.

Article quality underwent evaluation using the Heyland Methodological Quality Score (MQS) [14]. The highest score achievable was 18, distributed among randomization, analysis, blinding, selection, group comparability, degree of follow-up, treatment regimen, combined interventions, and outcome reporting, each receiving 2 points.

The risk of bias was assessed using SYRCLE's Risk of Bias in Animal Testing tool [15]. Evaluated elements encompassed sequence generation, implementation, detection, attrition, and reporting bias. An "unclear" designation was given in the absence of data, "high risk" when methodology potentially compromised result accuracy, and "low risk" when methodology was deemed not to influence outcomes.

2.5. Statistical Analysis

The analysis focused on changes in baseline values for the hydrogel injection and hydrogel combination treatment groups after myocardial infarction, specifically examining left ventricular functional and morphological outcomes. Data were presented as mean ± standard deviation (SD). When only mean and standard error were provided, we converted the standard error to standard deviation using the sample size. If a study had multiple intervention or control groups, we combined relevant outcome indicator groups, drawing from established literature methodologies to minimize analysis errors [16]. We used the inverse variance method and a random effects model for the pooled analysis in the data software. A 95% confidence interval was adopted, with significance set at P < 0.05.

Forest plots depicted relative treatment effects for each outcome indicator, along with their 95% CIs for individual studies, diverse combination therapy types, and the comprehensive random-effects meta-analysis for each parameter under consideration. To mitigate study heterogeneity, analyses were stratified based on animal size. Preliminary data analysis was executed using Review Manager (RevMan) 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark).

In the a priori subgroup analysis, we considered variables such as combination therapy (encompassing polytherapy and individual monotherapies), hydrogel source subtype, sex, intervals post-MI for both follow-up and treatment, MQS, general animal subtype, and specifically murine small animal subtype. For continuous variables like cell dose, duration, and MQS, dichotomous subgroup analyses employed the median value from all studies in the meta-analysis. When the study count reached or exceeded three, meta-regression analyses were conducted using STATA MP software v17 (StataCorp, College Station), with a significance threshold of P < 0.05P < 0.05 to determine the impact of subgroup variations.

Heterogeneity among included studies was assessed using the Cochran Q statistic, with significance identified at P < 0.10. The interpretation of I² values was as follows: I² < 50%, moderate heterogeneity; 50% ≤ I² ≤ 75%, substantial heterogeneity; I² > 75%, considerable heterogeneity¹⁶ Sensitivity analyses were conducted to investigate the potential sources of heterogeneity by systematically excluding individual trials.

Publication bias was assessed by visually examining funnel plot results supplemented with Begg's and Egger's statistical tests, where P < 0.05 was considered as evidence of a small study effect. At least 9 studies were included in assessing publication bias to meet standard literature requirements [17].

3.1. Search Results

The PRISMA review flowchart is shown in Fig. 1. Initially, searches of PubMed, Web of Science, Scopus, and Cochrane databases yielded 5230 pertinent articles. After title screening, 3345 articles were discarded. Of the 1885 articles subjected to title and abstract review, duplicates were removed, leaving 352 articles. Further full-text evaluation of these 352 articles led to the exclusion of 269 that did not align with inclusion and exclusion criteria. Consequently, 83 articles were retained for the analysis.

3.2. Study Characteristic

Table 1 presents the study characteristics. The meta-analysis primarily considered murine small animal models (N = 73; 88%), with rats (N = 54; 65.1%) and mice (N = 19; 22.9%) being predominant. Other models encompassed rabbits (N = 3; 3.6%), sheep (N = 2; 2.4%), and pigs (N = 6; 7.2%). Notably, one study utilized both rat and sheep models. Hydrogels from the selected studies fell into two categories: those of natural origin (N = 44;53%) and chemically synthesized ones (N = 39;47%). Hydrogels modified from natural material backbones were categorized as natural origin. Combination therapies predominantly featured monotherapy (N = 62;74.7%) and polytherapy (N = 21;25.3%), each further delineated due to variances in therapeutic effects. Monotherapy comprised cell therapy (N = 32;38.6%), cytokine therapy (N = 14;16.9%), drug therapy (N = 10;12%), extracellular vesicle therapy (N = 4;4.8%), and nucleic acid therapy (N = 2;2.4%). Most studies employed male animal models (N = 68; 81.9%), with 12 (14.5%) using females. All animal models followed the left coronary artery ligation method for myocardial infarction, ensuring consistent and reliable results. Most animal studies had a 4-week follow-up after intracardiac injection of therapeutic hydrogel, leading to autopsy (N = 65; 78.3%). In larger animals like sheep and pigs, the typical follow-up was extended to 8 weeks, with the longest being 52 weeks. Immediate hydrogel injection post-myocardial infarction modeling occurred in 73 studies (88%). Funding sources varied, with 58 studies (69.9%) jointly funded by institutions and companies, 19 (22.9%) by institutions alone, and 6 (7.2%) solely by companies. One study (1.1%) did not report its funding. Regarding geographical distribution, the studies were primarily based in China (46) and the United States (17). Other contributions included Canada (4), Taiwan China (3), Iran (2), Japan (2), Korea (2), and Singapore (2), with Denmark, France, Germany, and Italy each contributing one study.

Table 1

Characteristics of included studies
	Reference (study,year)	Animal	Total N	Age	Weight(SD)	Follow-up	Timing of Treatment (post-MI)	Baseline EF or FS (post-MI)	Encapsulation materials	Hydrogel	Funding Source	Setting
Rufaihah et al. 2013 [18]	Combined group	Rats	7F	Not reported	250g	4w	0	Not reported	VEGF-A	PEGylated fibrinogen hydrogel	Agency	Singapore
Rufaihah et al. 2013 [18]	Hydrogel group		7F
Rufaihah et al. 2017 [19]	Combined group	Rats	10M	Not reported	250-300g	4w	0	Not reported	VEGF་ANG-1	polyethylene glycol-fibrinogen (PF) hydrogels	Agency/Idustry	China
Rufaihah et al. 2017 [19]	Hydrogel group		10M
Rocker et al. 2022 [20]	Combined group	Mice	4	Not reported	24–28 g	4w	0	Not reported	VEGF + IL-10་PDGF	S-GC-PNIPAM hydrogel	Agency	USA
Rocker et al. 2022 [20]	Hydrogel group		4
Steele et al. 2017 [21]	Combined group	Rats	10M	Not reported	250–300 g	4w	0	Not reported	HGFdf	PEG-PNIPAM-P1 hydrogel	Agency	USA
Steele et al. 2017 [21]	Hydrogel group		10M
Steele et al. 2020 [22]	Combined group	Rats	12M	Not reported	250-300g	4w	0	Not reported	HGFdf + ESA 1α	hydhyaluronic acid poly(ethyleneglycol) poly(lactic acid) hydrogel	Agency	USA
Steele et al. 2020 [22]	Hydrogel group		12M
Steele et al. 2020 [22]	Combined group	Sheep	7M	Not reported		8w	0	Not reported	HGFdf + ESA 1α	hydhyaluronic acid poly(ethyleneglycol) poly(lactic acid) hydrogel	Agency	USA
Steele et al. 2020 [22]	Hydrogel group		7M
Chow et al. 2017 [23]	Combined group	Rats	5M	8weeks		10w	0	EF = 45.4 ± 7.8	Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte	PEG hydrogel	Agency/Idustry	UK
Chow et al. 2017 [23]	Hydrogel group		6 M
Gaffey et al. 2015 [24]	Combined group	Rats	10M	Not reported	250-300g	4w	0	Not reported	Rat bone marrow-derived endothelial progenitor cells	hyaluronic acid hydrogel		USA
Gaffey et al. 2015 [24]	Hydrogel group		10M
Hakravarti et al. 2018 [25]	Combined group	Mice	4F	12weeks		3w	0	Not reported	Human adipose-derived stem cells	gelatin methacrylamide (GelMA)	Agency	USA
Hakravarti et al. 2018 [25]	Hydrogel group		4F
Paul et al. 2014 [26]	Combined group	Rats	7M	Not reported	200-250g	2w	0	EF = 36.6	Graphene oxide + VEGF	GelMA hydrogel	Agency/Idustry	USA
Paul et al. 2014 [26]	Hydrogel group		7M
Qian et al. 2022 [27]	Combined group	Rats	8M	Not reported	Not reported	4w	0w	Not reported	platelet concentrates including PRP	ALG-HA hydrogels	Agency/Idustry	China
Qian et al. 2022 [27]	Hydrogel group		8M
Xu et al. 2017 [28]	Combined group	Rats	6M	Not reported	225-250g	4w	1w	Not reported	rat bone-marrow mesenchymal stem cells	chitosan hydrogel	Agency	China
Xu et al. 2017 [28]	Hydrogel group		6M
Follin et al. 2018 [29]	Combined group	Rats	13M	Not reported	266 ± 15 g	4w	0w	EF = 45.04 ± 9.08	adipose-derived Mesenchymal stem cell	Alginate Hydrogel	Agency	Denmark
Follin et al. 2018 [29]	Hydrogel group		10M
Fu et al. 2022 [30]	Combined group	Rats	10M	8weeks	200–250 g	4w	0w		bFGF	CMCS-S-S-Py and rBSA hydrogel	Agency/Idustry	China
Fu et al. 2022 [30]	Hydrogel group		10M
Purcell et al. 2018 [31]	Combined group	Pigs	7M	Not reported	20000g	4w	0w	Not reported	rTIMP-3	hyaluronic acid (HA)-based hydrogel	Agency	USA
Purcell et al. 2018 [31]	Hydrogel group		7M
Purcell et al. 2014 [32]	Combined group	Pigs	7M	Not reported	25000g	4w	0w	Not reported	rTIMP-3	Dextran sulphate (DS) / ALD modification of its diol groups hydrogels	Agency/Idustry	USA
Purcell et al. 2014 [32]	Hydrogel group		7M
Cimenci et al. 2022 [33]	Combined group	Mice	7F	Not reported	Not reported	5w	0w	Not reported	fisetin	thermoresponsive collagen hydrogel	Agency/Idustry	Canada
Cimenci et al. 2022 [33]	Hydrogel group		7F
Fan et al. 2019 [34]	Combined group	Rats	12F	Not reported	200-220g	4w	0w	Not reported	GST-TIMP-bFGF	collagen-GSH hydrogel	Agency/Idustry	China
Fan et al. 2019 [34]	Hydrogel group		12F
Chen et al. 2018 [35]	Combined group	Rats	11M	Not reported	350-375g	5w	0w	Not reported	EPCs EVs	adamantane-modified HA (Ad-HA) and β-cyclodextrin-modified HA (CD-HA) shear-thinning hydrogel (STG)	Agency/Idustry	USA
Chen et al. 2018 [35]	Hydrogel group		10M
Kim et al. 2020 [36]	Combined group	Mice	9M	7weeks	20-22g	4w	0w	Not reported	MSC	gelatin–hydroxyphenyl propionic acid (GH) hydrogels	Agency	Korea
Kim et al. 2020 [36]	Hydrogel group		9M
Han et al. 2019 [36]	Combined group	Rats	5M			4w	0w	Not reported	UMSC exosomes	(PA-GHRPS and NapFF) PGN hydrogel	Agency/Idustry	China
Han et al. 2019 [36]	Hydrogel group		5M
Chen et al. 2013 [37]	Combined group	Rats	8M	6weeks	200-250g	4w	0w	EF = 37.9	allogeneic bone marrow mononuclear cells	hyaluronan (HA) hydrogel	Agency/Idustry	Taiwan of China
Chen et al. 2013 [37]	Hydrogel group		8M
Chen et al. 2014 [38]	Combined group	Pigs	7	Not reported	Not reported	8w	0w	EF = 45.8	bone marrow mononuclear cells	hyaluronan (HA) hydrogel	Agency/Idustry	Taiwan of China
Chen et al. 2014 [38]	Hydrogel group		8
Hydrogel group		8M
Mathieu et al. 2012 [40]	Combined group	Rats	9F	Not reported	180-190g	8w	0w	Not reported	rat bone-marrow mesenchymal stem cells	Silanized-Hydroxypropyl Methyicellulose hydrogel	Agency/Idustry	France
Mathieu et al. 2012 [40]	Hydrogel group		7F
Xu et al. 2014 [41]	Combined group	Rats	5F	Not reported	150-200g	4w	0w	Not reported	Rat bone marrow mesenchymal stem cells	Col-SH/OAC-PEG-OAC hybrid hydrogels	Agency/Idustry	China
Xu et al. 2014 [41]	Hydrogel group		5F
Chen et al. 2017 [42]	Combined group	Mice	6M	8-11weeks		2w	0w	Not reported	Curcumin + NO	FFE-ss-ERGD hydrogels	Agency/Idustry	China
Chen et al. 2017 [42]	Hydrogel group		6M
Awada et al. 2017 [43]	Combined group	Rats	8M	6-7weeks	175-225g	8w	0w	Not reported	TIMP-3 + FGF-2 + SDF-1α	fibrin gel hydrogels	Agency	USA
Awada et al. 2017 [43]	Hydrogel group		8M
Wang et al. 2010 [44]	Combined group	Rats	8F	6weeks		4w	0w	Not reported	bFGF	chitosan hydrogel	Agency/Idustry	China
Wang et al. 2010 [44]	Hydrogel group		8F
Wang et al. 2012 [45]	Combined group	Rats	32F	6weeks		4w	1w	Not reported	mouse embryonic stem cells	OPF hydrogels [ fumaryl chloride and poly(ethylene glycol) (PEG)]	Agency	USA
Wang et al. 2012 [45]	Hydrogel group		24F
Wang et al. 2014 [46]	Combined group	Rats	20M	Not reported	250 ± 10g	4w	0w	Not reported	CD29 Rat brown adipose-derived stem cells	chitosan hydrogel	Agency/Idustry	China
Wang et al. 2014 [46]	Hydrogel group		20M
Ding et al. 2020 [47]	Combined group	Rats	6M	Not reported	250g	4w	0w	EF = 42.4 FS = 21.9	mesenchymal stem cells	methacrylate hyaluronic acid hydrogel	Agency/Idustry	China
Ding et al. 2020 [47]	Hydrogel group		6M
Li et al. 2018 [48]	Combined group	Mice	4M	8–10weeks	20 ± 5g	4w	0w	Not reported	Mouse Induced pluripotent stem (MiPS) cells	folic acid (FA) Hydrogel	Agency/Idustry	China
Li et al. 2018 [48]	Hydrogel group		4M
Zhu et al. 2017 [49]	Combined group	Rats	7M	8-10weeks	200-250g	4w	0w	Not reported	bFGF	DexPCLHEMA/PNIPAAm hydrogel	Agency/Idustry	China
Zhu et al. 2017 [49]	Hydrogel group		7M
Cohen et al. 2014 [50]	Combined group	Mice	5M	10weeks	25-30g	2w	0w	Not reported	Neuregulin-1β	hyaluronate hydrogel	Agency	USA
Cohen et al. 2014 [50]	Hydrogel group		5M
Cohen et al. 2020 [22]	Combined group	Sheep	6M	26-30weeks	35000-40000g	8w	0w	Not reported	Neuregulin-1β	hyaluronate hydrogel	Agency	USA
Cohen et al. 2020 [22]	Hydrogel group		4M
Ding et al. 2020 [51]	Combined group	Rats	5M	8weeks	200-250g	4w	0w	Not reported	catalase + hyperbranched polymers	Reactive Oxygen Species Scavenging and O2 Generating Injectable Hydrogel/hyaluronic acid (HA-MA)	Agency/Idustry	China
Ding et al. 2020 [51]	Hydrogel group		5M
Zhou et al. 2021 [52]	Combined group	Rats	10M	Not reported	250 ± 10g	4w	0w	Not reported	melanin	Alginate (Alg) hydrogels	Agency/Idustry	China
Zhou et al. 2021 [52]	Hydrogel group		10M
Chen et al. 2021 [53]	Combined group	Rats	4M	6-8weeks	220-250g	4w	0w	Not reported	Astragaloside IV	(PEGDA-PBA) - (HA-SH) hydrogel	Agency/Idustry	China
Chen et al. 2021 [53]	Hydrogel group		4M
Chen et al. 2014 [54]	Combined group	Rabbits	7M	Not reported	2200-2600g	4w	1w	EF = 56.13 ± 7.51	Rabbit bone marrow stem cells	α-cylcodextrin/MPEG–PCL–MPEG hydrogel	Idustry	China
Chen et al. 2014 [54]	Hydrogel group		7M
Wu et al. 2011 [55]	Combined group	Rats	10	Not reported	200-250g	5w	1w	FS = 28.9	VEGF	PVL-b-PEG-b-PVL/aliphatic polyester hydrogel (HG)	Agency/Idustry	Canada
Wu et al. 2011 [55]	Hydrogel group		11
Khan et al. 2022 [56]	Combined group	Rats	9F	Not reported	250-300g	4w	0w	Not reported	hAMSC/amniotic stromal mesenchymal stem cells	chitosan and hyaluronic acid (C/HA) based hydrogel	Agency	Canada
Khan et al. 2022 [56]	Hydrogel group		10F
Cheng et al. 2012 [57]	Combined group	Mice	8M	10-12weeks	Not reported	3w	0w	EF = 31.8	Cardiosphere-derived cells (CDCs)	hyaluronan and porcine gelatin hydrogel	Agency	USA
Cheng et al. 2012 [57]	Hydrogel group		8M
Zhu et al. 2022 [58]	Combined group	Rats	6M	Not reported	200g	4w	0w	Not reported	Mesenchymal stem cell and 68Ga3 + cations	GNR@SNs/PLGA-PEG-PLGA hydrogel	Agency/Idustry	China
Zhu et al. 2022 [58]	Hydrogel group		6M
Wu et al. 2023 [59]	Combined group	Mice	6M	8weeks	22-25g	4w	0w	EF = 37.55 FS = 19	SDF-1/CMs	dECM hydrogel	Agency/Idustry	China
Wu et al. 2023 [59]	Hydrogel group		6M
Montazeri et al. 2020 [60]	Combined group	Rats	5M	8weeks	250–300g	4w	0w	Not reported	vascular endothelial growth factor (VEGF)/ hESC-CPC-derived cardiomyocytes	fibrin hydrogel	Agency/Idustry	Iran
Montazeri et al. 2020 [60]	Hydrogel group		5M
Reis et al. 2015 [61]	Combined group	Rats	7M	Not reported	200–250 g	6w	0w	Not reported	prosurvival angiopoietin-1–derived peptide, QHREDGS	chitosan-collagen hydrogel	Agency/Idustry	Canada
Reis et al. 2015 [61]	Hydrogel group		7M
Liu et al. 2020 [62]	Combined group	Mice	8	Not reported	Not reported	4w	0w	Not reported	bone marrow-derived Mesenchymal stem cell	chitosan (CS) thermosensitive hydrogel	Agency/Idustry	China
Liu et al. 2020 [62]	Hydrogel group		8
Vong et al. 2018 [63]	Combined group	Mice	6M	7-8weeks	32–35 g	4w	0w	Not reported	NO	PMNT-PEG-PMNT PArg-PEG-PArg་PAAc	Agency/Idustry	Japan
Vong et al. 2018 [63]	Hydrogel group		6M
Gao et al. 2020 [64]	Combined group	Mice	5M	8-10weeks	Not reported	4w	0w	Not reported	Mesenchymal stem cells	bioglass (BG)/γ-polyglutamic acid/chitosan hydrogel	Agency/Idustry	China
Gao et al. 2020 [64]	Hydrogel group		5M
Ciuffreda et al. 2018 [65]	Combined group	Rats	10F	Not reported	Not reported	4w	1w	EF25.14 ± 4.15 FS30.90 ± 4.68	rat bone-marrow MSC	polyethylene glycol (PEG)-based hydrogel containing heparin (H-HG)	Agency	Italy
Ciuffreda et al. 2018 [65]	Hydrogel group		10F
Chang et al. 2016 [66]	Combined group	Pigs	6M	20weeks	22.26 ± 0.78kg	8w	0w	EF = 47.5	human cord blood mononuclear cells	hyaluronan (HA) hydrogel	Agency/Idustry	Taiwan of China
Chang et al. 2016 [66]	Hydrogel group		6M
Chen et al. 2019 [67]	Combined group	Rats	10M	Not reported	Not reported	4w	0w	Not reported	IL-10	AdHA and CDHA hydrogel	Agency/Idustry	USA
Chen et al. 2019 [67]	Hydrogel group		8M
Song et al. 2014 [68]	Combined group	Rats	10M	6weeks	Not reported	4w	0w	Not reported	stem cell homing factor (SDF-1) angiogenic peptides	Biomimetic hyaluronic acid based hydrogel	Agency	Korea
Song et al. 2014 [68]	Hydrogel group		10M
Qi et al. 2020 [69]	Combined group	Rats	8M	Not reported	200-250g	4w	1w	Not reported	Bioglass	Alginate hydrogel	Agency/Idustry	China
Qi et al. 2020 [69]	Hydrogel group		8M
Bao et al. 2017 [70]	Combined group	Rats	13M	Not reported	250 ± 20g	4w	0w	Not reported	adipose tissue-derived stromal cells	PEG-MEL/HA-SH/GO hydrogels	Agency/Idustry	China
Bao et al. 2017 [70]	Hydrogel group		13M
Firoozi et al. 2020 [71]	Combined group	Rats	6M	Not reported	280-350g	4w	0w	Not reported	human bone marrow-derived mesenchymal stem cells	(RADA)4-SDKP hydrogel	Agency/Idustry	Iran
Firoozi et al. 2020 [71]	Hydrogel group		6M
Shafei et al. 2022 [72]	Combined group	Rats	6M	12weeks	250-280g	4w	0w	FS = 30	microRNA-126/146a mimics in exosomes	alginate hydrogel	Agency	USA
Shafei et al. 2022 [72]	Hydrogel group		6M
Lü et al. 2010 [73]	Combined group	Rats	10M	6weeks	Not reported	4w	1w	Not reported	nuclear-transferred embryonic stem cells	temperature-responsive chitosan hydrogel	Agency/Idustry	China
Lü et al. 2010 [73]	Hydrogel group		10M
Zhu et al. 2022 [58]	Combined group	Rats	10M	6weeks	Not reported	4w	0w	Not reported	Umbilical cord mesenchymal stem cells	GelMA-O5/rGO hydrogels	Agency/Idustry	China
Zhu et al. 2022 [58]	Hydrogel group		10M
Bao et al. 2023 [74]	Combined group	Rats	5M	Not reported	200-220g	4w	1w	Not reported	superparamagnetic iron oxide (SPIO)	chitosan/β-glycerophosphate (CS/GP) hydrogel	Agency/Idustry	China
Bao et al. 2023 [74]	Hydrogel group		5M
Wang et al. 2009 [75]	Combined group	Rats	12M	Not reported	200–250g	4w	0w	Not reported	recombined human erythropoietin	α-cyclodextrin/MPEG–PCL–MPEG hydrogel	Agency	China
Wang et al. 2009 [75]	Hydrogel group		12M
Wang et al. 2009 [76]	Combined group	Rabbits	8M	Not reported	2200–2600g	4w	0w	Not reported	Bone marrow stem cells	α-cyclodextrin/MPEG–PCL–MPEG hydrogel	Agency/Idustry	China
Wang et al. 2009 [76]	Hydrogel group		8M
Vu et al. 2015 [77]	Combined group	Pigs	6M	Not reported	65000-70000g	8w	0w	Not reported	PRP, allopurinol, ascorbic acid and ibuprofen	Gelatin hydrogel	Agency	Singapore
Vu et al. 2015 [77]	Hydrogel group		6M
Kraehenbuehl et al. 2011 [78]	Combined group	Rats	8M	Not reported	200-250g	6w	0w	EF = 52.7	hESC-derived ELC + SMLC + Tβ4	PEG-hydrogels	Agency/Idustry	USA
Kraehenbuehl et al. 2011 [78]	Hydrogel group		8M
Wan et al. 2014 [79]	Combined group	Rats	14M	Not reported	200-250g	4w	0w	Not reported	short-hairpin RNA of angiotensin	(Dex-PCL-HEMA/PNIPAAm) hydrogel	Agency/Idustry	China
Wan et al. 2014 [79]	Hydrogel group		14M
Wang et al. 2018 [80]	Combined group	Rats	17M	Not reported	250 ± 20g	6w	0w	Not reported	plasmid DNA-eNOs + ADSCs	TA-PEG/HA-SH hydrogels	Agency/Idustry	China
Wang et al. 2018 [80]	Hydrogel group		16M
Lu et al. 2009 [81]	Combined group	Rats	12F	Not reported	Not reported	4w	1w	Not reported	Mouse embryonic stem cells	temperature-responsive chitosan hydrogel	Agency/Idustry	China
Lu et al. 2009 [81]	Hydrogel group		13F
Li et al. 2014 [82]	Combined group	Rats	6M	Not reported	250 ± 20g	4w	0w	Not reported	Rat brown adipose-derived stem cells	SWCNTs-modified PNIPAAm hydrogel	Agency/Idustry	China
Li et al. 2014 [82]	Hydrogel group		6M
Li et al. 2010 [83]	Combined group	Rabbits	11M	Not reported	2000–2500g	4w	1w	Not reported	bone marrow-derived mononuclear cells	Dex-PCL-HEMA/PNIPAAm hydrogel	Agency/Idustry	China
Li et al. 2010 [83]	Hydrogel group		8M
Hu et al. 2022 [84]	Combined group	Mice	5M	8-10weeks		4w	0w	Not reported	ISL1-Mesenchymal stem cell-Exo	angiogenin-1 hydrogel (Ang-1 gel)	Agency/Idustry	China
Hu et al. 2022 [84]	Hydrogel group		5M
Li et al. 2021 [85]	Combined group	Pigs	6M	Not reported	45000-50000g	4w	0w	EF = 35	MSN / miR-21-5p	gelatin hydrogels	Agency/Idustry	China
Li et al. 2021 [85]	Hydrogel group		6M
Liu et al. 2021 [86]	Combined group	Rats	20M	6-8weeks	200 ± 10g	4w	0w	Not reported	puerarin + rBMesenchymal stem cell	hyaluronic acid (HA-Tyr) hydrogel	Agency/Idustry	China
Liu et al. 2021 [86]	Hydrogel group		20M
Wu et al. 2021 [87]	Combined group	Mice	15M	8weeks	22-25g	4w	0w	Not reported	VEGF and B/SF microspheres	alginate based composite hydrogel	Agency/Idustry	China
Wu et al. 2021 [87]	Hydrogel group		15M
Chen et al. 2020 [88]	Combined group	Mice	20M	8-12weeks		4w	0w	EF = 36.4	Rat adipose-derived mesenchymal stem cells	Col-Transglutaminase cross-linked gelatin	Agency/Idustry	China
Chen et al. 2020 [88]	Hydrogel group		20M
Zhang et al. 2021 [89]	Combined group	Mice	5M		22-28g	4w	0w	Not reported	Dendritic cell-derived exosomes (DEXs)	Alginate hydrogel	Agency/Idustry	China
Zhang et al. 2021 [89]	Hydrogel group		5M
Chen et al. 2020 [90]	Combined group	Mice	13M	6weeks		4w	0w	Not reported	colchicine	(PLGA–PEG–PLGA) hydrogel	Agency/Idustry	China
Chen et al. 2020 [90]	Hydrogel group		11M
Xia et al. 2015 [91]	Combined group	Mice	8F	Not reported	Not reported	4w	0w	Not reported	Mouse bone marrow mesenchymal stem cells	poly(NIPAAm-co-HEMA-co-HEMAPCL)-type I collagen hydrogel	Agency	China
Xia et al. 2015 [91]	Hydrogel group		8F
	Lyu et al. 2020
	Combined group	Rats	5M	Not reported	220 ± 20g	4w	0w	Not reported	MSC aggregates (FMAs) hMesenchymal stem cell་PLGA	OHA@HHA hydrogel	Agency/Idustry	China
	Hydrogel group		5M
Sakakibara et al. 2002 [92]	Combined group	Rats	10M	Not reported	250-290g	4w	1w	FS = 19.8 ± 4.1	bFGF་ fetal cardiomyocyte	gelatin hydrogels	Agency	Japan
Sakakibara et al. 2002 [92]	Hydrogel group
Zheng et al. 2022 [93]	Combined group	Rats	3M	Not reported	250 ± 20g	4w	0w	Not reported	bone mesenchymal stem cells (BMesenchymal stem cell)/KLT ( a VEGF mimetic peptide with pro-angiogenic effects)	MaHA/B-G-SH/Fe3 + hydrogels	Agency/Idustry	China
Zheng et al. 2022 [93]	Hydrogel group		3M
Zheng et al. 2022 [94]	Combined group	Rats	3M	Not reported	250 ± 20g	4w	0w	Not reported	S1P SS-31(plasma enzyme-degradable peptide)/Lipo	PAMB-G-TK/4-Arm-PEG-SG Hydrogels	Agency/Idustry	China
Zheng et al. 2022 [94]	Hydrogel group		3M
Liu et al. 2012 [95]	Combined group	Rats	22M	Not reported	Not reported	4w	0w	Not reported	Rat adipose-derived mesenchymal stem cells	chitosan hydrogel	Agency/Idustry	China
Liu et al. 2012 [95]	Hydrogel group
Yuan et al. 2019 [96]	Combined group	Rats	8M	9–10weeks	200 ± 20g	4w	0w	Not reported	Mydgf	citrate-containing polyester hydrogel (PPC-ET/PEG Hydrogels)	Agency/Idustry	China
Yuan et al. 2019 [96]	Hydrogel group

3.3. Quality and Risk of Bias Assessment

To evaluate the quality of the included literature, scores ≥ 11 were designated as high-quality based on the MQS analysis (Supplement Table Ⅲ). Out of the assessed literature, 66 articles (69.5%) were deemed high-quality, while only 25 (25.8%) explicitly mentioned a blinded analysis of outcome indicators.

Risk of bias plot analysis (Supplement Fig. Ⅰ) indicated a high risk of bias among the included literature. Only 30 trials (36.1%) maintained blinding during outcome measurement. Most trials neither specified a blinding protocol nor implemented blinding concerning the animal housing environment and group allocation, reflecting a pronounced risk of bias. No trials were omitted from the primary analysis due to quality or bias concerns.

3.4. Effect of Injectable Hydrogel Combination Therapy on Cardiac Function

Injectable hydrogels, when combined with other therapies, yielded notable improvements in left ventricular Ejection Fraction (EF: Fig. 2) and Fractional Shortening (FS: Fig. 3), registering a mean difference (MD) of 11.81 [95% CI: 10.38, 13.24] and 6.25% [95% CI: 5.98, 6.52], respectively, in murine small animal models compared to hydrogels alone.

Cytarabine emerged as the predominant therapy, stabilizing enhancements in both Ejection Fraction (MD = 11.81 [95% CI: 10.38, 13.24]) and Fractional Shortening (MD = 6.78% [95% CI: 6.41, 7.16]).

Exosomes exhibited the most significant improvements, with Ejection Fraction at MD = 16.53% [95% CI: 9.33, 33.74] and Fractional Shortening at MD = 15.38% [95% CI: 12.40, 18.36], though a limited sample size necessitates further validation.

Multitherapy achieved marked results in Ejection Fraction (MD = 12.07% [95% CI: 8.75, 15.38]) and short axis shortening (MD = 7.00% [95% CI: 6.35, 7.65]) (Supplementary Fig. Ⅱ).

Regarding the secondary outcomes, analysis of ESV, EDV, ESD, EDD, infarct size and wall thickness consistently demonstrated superior treatment outcomes with hydrogel combination therapy compared to the sole hydrogel injection (Online Supplementary Fig. II). Injectable hydrogel combined with multidrug therapy exhibited consistent improvements across all parameters: EDD: MD = -0.02 mm [95% CI: -0.07, -0.02], ESD: MD = -1.18 mm [95% CI: -1.82, -0.54], EDV: MD = -0.07 mL [95% CI: -0.18, -0.03], ESV: MD = -0.07 mL [95% CI: -0.11, -0.03], infarct size: MD = -12.79% [95% CI: -16.44, -9.15], wall thickness: MD = 0.57 mm [95% CI: 0.35, 0.79]). The second highest was in combination with cellular therapy (EDD: MD = -0.02 mm [95% CI: -0.07, -0.02], ESD: MD = -1.18 mm [95% CI: -1.82, -0.54], EDV: MD = -0.07 mL [95% CI: -0.18, -0.03], ESV: MD = -0.07 mL [95% CI: -0.11, -0.03], infarct size: MD = -12.79% [95% CI: -16.44, -9.15], wall thickness: MD = 0.57 mm [95% CI: 0.35, 0.79]).

In non-murine studies, the classification and analysis of animal types revealed a notable improvement in EF, recording an MD of 8.49% [95% CI: 7.46, 9.53]. The pig model, boasting a substantial sample size, exhibited the most pronounced effect, with an MD of 9.09% [95% CI: 7.89, 10.29]. However, secondary outcomes such as FS, ESV, EDV, ESD, EDD, infarct area, and ventricular wall thickness were either unreported or scarcely represented, precluding any correlation analysis.

3.5. Subgroup Analysis

Given the variety of animal models, animal volume size significantly influences outcome indicator analysis. A subgroup analysis was conducted for precision, focusing predominantly on murine small animal models. This subgroup analysis of LV Ejection Fraction encompassed sex, combination therapy, treatment duration, follow-up duration, small animal model type, hydrogel classification, and MQS.

Subgroup analysis of combination therapy revealed that extracellular vesicular therapy, with an MD of 16.53% [95% CI: 9.33, 33.74] (P < 0.005), significantly outperformed drug therapy, cytokine therapy, and cytarabine therapy. Following closely behind extracellular vesicular therapy in efficacy was polypharmacy, which, despite its significance (P < 0.005), offered a larger sample size and a more consistent effect. Analyzing follow-up durations highlighted that a 4-week span (P < 0.005) yielded the most optimal overall impact, underscoring the significance of follow-up time on outcome indicators.

Regarding factors such as sex, animal mass, treatment duration, creature subtype, and hydrogel origin, no significant alterations in effects were observed. Outcomes from the Fractional Shortening subgroup analysis mirrored those of the Ejection Fraction. However, it's worth highlighting that, within the combined therapy analysis, cellular therapy (P < 0.005) demonstrated a slight edge over Multitherapy (P < 0.005) in enhancing Fractional Shortening.

The available data was insufficient for certain outcome indicators to conduct a detailed subgroup regression analysis. However, where adequate data existed, the analysis revealed the influence of hydrogel type on each metric. Distinct effects were observed between natural sources and chemically synthesized hydrogels across two cardiac function and morphological indicators. Parameters such as treatment duration, follow-up timeframe, and varied combination therapies profoundly influenced treatment outcomes (Supplementary Fig. Ⅲ-Ⅷ).

3.6. Publication Bias

Funnel plot analyses for primary outcomes in a murine small animal model indicated significant publication bias. The funnel plots for EF and FS displayed an asymmetrical distribution. Both Begg's and Egger's tests identified publication bias in EF (P = 0.001). Furthermore, Egger's test pinpointed bias in FS (P = 0.007) (Fig. 6). Considering the differences in the results of FS (Begg's test P = 0.575, Egger's test P = 0.007), we refer to Egger's test due to its slightly higher test efficacy.

The funnel plots in other secondary indicators revealed publication bias in all metrics except for End Diastolic Volume, which did not show publication bias.

In large animal trials, the funnel plot for EF displayed no evident asymmetry (Online Supplementary Fig. X). Both Egger's and Begg's tests detected no significant publication bias for EF, with values of P = 0.39 and P = 1.000 respectively. Data was insufficient to assess publication bias for FS and other secondary metrics in these trials.

Few systematic evaluations and meta-analyses have been conducted on the therapeutic efficacy of injectable hydrogels for infarcted myocardium. An earlier systematic review examining various biological scaffolds (including injectable hydrogels, microspheres, and patches) in tandem with stem cell delivery to the infarcted myocardium found injectable hydrogels superior to other scaffold types.[142] Therefore, our study delved deeper into injectable hydrogels. We analyzed 83 pertinent publications, focusing on cardiac morphological and functional indices assessed at the end of the follow-up period in animal models of myocardial infarction created via left coronary artery ligation. These evaluations considered combinations of chemically synthesized hydrogels or naturally derived hydrogels with various therapies using a control group of hydrogel alone. Our results revealed that the combination of injectable hydrogel and therapy significantly enhanced primary outcomes, Ejection Fraction and left ventricular short axis shortening rate, compared to the hydrogel injection. Secondary outcomes, including ESD, EDD, ESV, EDV, wall thickness, and infarct size, also showed marked improvement. Subgroup analyses suggested limited literature on extracellular vesicle therapy, challenging confident conclusions. Cellular therapies, particularly those involving stem cells, exhibited consistent effects. While polypharmacy entails a combination of various therapies, making refined classification challenging, it's evident that its combined effect surpasses that of cellular therapy. Furthermore, employing targeted therapies at each stage of myocardial infarction can offer a comprehensive approach and warrants further exploration.

4.1. Monotherapy

4.1.1. Cellular therapy

Cell therapy, predominantly stem cell therapy, remains a prevalent focus of current combination therapy research [97, 98]. The literature primarily highlights mesenchymal stem cells [62], monocytes [37], embryonic stem cells [45], and human induced pluripotent stem cells [23]. Combining stem cell therapy with hydrogel protocols has applications in spinal cord injury repair [99, 100], osteoarthritis treatment [101], chronic diabetic wound healing [102], cardiovascular disease treatment [103, 104], and hind limb ischemia treatment [105]. Mesenchymal stem cells (MSCs) [106] emerge as promising, given their ease of isolation, robust proliferative capacity, immunomodulatory ability, and diverse differentiation potential [107]. Many studies encapsulate MSCs from varied sources (e.g., bone marrow, adipose tissue, umbilical cord blood) within hydrogels. Enhanced paracrine secretion by MSCs plays a pivotal role in the effective repair of cardiac tissue [108]. However, some research suggests that encapsulation can influence stem cell proliferation and paracrine capability, potentially due to limited intercellular interactions in hydrogels, leading to reduced cytokine secretion [109]. MSCs were pre-treated using physicochemical environments (hypoxia [110], hyperoxia [111], hydrogen sulfide [112]), pharmacological modifications (trimetazidine [113], lipopolysaccharide [114]), and genetic modifications (CXCR4 [115], SDF-1 [116], and HGF [117]) to enhance the paracrine mechanism of MSCs. Yuanning Lyu et al. [118] utilized a combination of human E-cadherin fusion protein (hE-cad-Fc)-encapsulated poly (lactic-co-glycolic acid) (PLGA) particles (hE-cad-PLGA) and human mesenchymal stem cells (hMSCs) to form 3D cell aggregates, which were then incorporated into hyaluronic acid (HA)-based hydrogels. Zhiye Wu et al¹¹⁸ used hepatocyte growth factor (HGF)-modified MSCs mounted on a class of small molecule hydrogels, which increased Bcl-2 and decreased Bax and cystein-3 levels, promoting MSC growth and proliferation and inhibiting apoptosis of cardiomyocytes in the lesioned areas. Additionally, the pretreatment of MSCs proved more effective than the study without pretreatment. In conclusion, the combination of cell therapy and hydrogel in the treatment of heart attacks has demonstrated significant therapeutic effects. This approach offers advantages in promoting tissue regeneration and facilitating healing in myocardial infarction areas through various stem cells or immune cells. To address potential issues with cell therapy, related studies have explored extracellular vesicle therapy or cytokine therapy as alternative approaches that can mitigate immunogenicity concerns [119].

4.1.2. Cytokine therapy

Cytokines (CK) are low-molecular-weight soluble proteins secreted by various cells, involved in immune regulation, cell growth, and tissue repair [120]. They can be classified as interleukins, interferons, tumor necrosis factor superfamily, colony-stimulating factors, chemokines, and growth factors. Central to both innate and adaptive immune systems, cytokines facilitate cell proliferation and activation and maintain physiological roles [121]. Jeffrey E. Cohen et al. [22] demonstrated improved ventricular function under ischemic conditions by anchoring epidermal growth factor neuromodulatory protein (NRG) to gelatin hydrogels, thereby stimulating cardiomyocyte mitogenic activity, curtailing apoptosis, and enhancing ischemic ventricular function. Other regimens predominantly employ combinations of growth factors such as VEGF, bFGF, and HGF. Given the intricate post-ischemic myocardial environment, cytokines alone might not offer comprehensive repair. Forest plot data suggest that cytokine therapy lags behind other treatments regarding morphological outcomes post-myocardial infarction. Thus, multifactor combinations or integration of diverse therapies are often preferred, a topic further explored in the subsequent Multitherapy therapy section.

4.1.3. Extracellular vesicle therapy

Extracellular vesicles, nanoscale vesicles resulting from paracellular secretion, are prevalent in animal extracellular fluids [122]. Related studies have shown that beneficial exosomes have been extracted from plants [123]. These vesicles encompass diverse biologically active components and boast properties like immunomodulation, low antigenicity, and tissue protection [124]. A subset of these vesicles, exosomes, carry biologically active biomolecules such as proteins, nucleic acids, lipids, and sugars, offering a spectrum of biological functions [125]. Their capability to act as nanocarriers facilitates cell-mediated drug delivery, maximizing therapeutic efficacy. Notably, certain exosomal proteins exhibit selective homing abilities, enhancing delivery efficiency [126]. The yield of exosomes is influenced by cell type, with immune cells often producing consistent yields that are therapeutically potent. Clinical trials have employed exosomes in diagnosing and treating various diseases [127–129].

In myocardial infarction, it's vital to acknowledge that directly injected exosomes might be swiftly cleared due to the myocardial environment. Consequently, injectable hydrogel scaffolds have gained research traction to enhance extracellular vesicle retention. Carol W Chen et al. [35] demonstrated that extracellular vesicles, isolated from endothelial progenitor cells and anchored to shear-thinning hydrogels, foster angiogenesis, support functional recovery, and mitigate adverse ventricular remodeling post-infarction. Current findings suggest that the therapeutic impact of MSCs may stem more from their paracrine release (encompassing cytokines, growth factors, and exosomes) than from their direct cellular effects [130, 131]. Renae Waters et al. [25] employed lipid-derived mesenchymal stem cells on methacrylate-based gelatin nanocomposite scaffolds, achieving sustained release of pivotal therapeutic growth factors that promote angiogenesis, scar reduction, and cardioprotection. Youming Zhang et al. [89] utilized dendritic cell-derived exosomes on alginate hydrogels, revealing enhanced Treg cell upregulation, M2 macrophage polarization, inflammation reduction, and cardiac protection post-myocardial infarction. In summary, extracellular vesicle therapy, based on cellular therapy, harnesses the paracrine/autocrine mechanisms of MSCs, predominantly mediated by exosomes. These vesicles perform key roles such as apoptosis reduction, inflammation alleviation, angiogenesis promotion, fibrosis inhibition, and tissue repair augmentation. This meta-analysis indicates the superiority of extracellular vesicle experiments over other methods in myocardial functional recovery. However, the morphological recovery remains constrained, and a broader scope of studies is essential given the limited literature in this domain. Challenges for extracellular vesicle development persist, notably the intricate isolation procedures and suboptimal yields [132].

4.1.4. Drug therapy

Medications used in tandem with hydrogel for myocardial infarction treatment span a broad spectrum, encompassing natural bioactive drugs (tanshin, colchicine [90], curcumin [133]), compounds (NO [134], Se [135]), and various synthetic products. Bioactive drugs, including curcumin and quercetin, exhibit potent anti-inflammatory, anti-apoptotic, and tissue repair properties. However, their limited aqueous solubility hinders efficient delivery through oral or traditional methods. Cui Yang et al. [135] employed Se-containing PEG-PPG hydrogels to diminish pro-inflammatory cytokine secretion, ameliorate myocardial fibrosis, and enhance left ventricular remodeling.

The shared trait among drugs examined in this section is their demonstrated benefits in treating cardiovascular diseases [133, 136]. However, their long-term effectiveness is often compromised by delivery challenges. Hydrogels facilitate sustained drug release [9], enhancing local pharmacological benefits while minimizing systemic side effects. This approach is more adept at addressing the prolonged and multifaceted pathological environment [137–139].

4.1.5. Nucleic acid therapy

Nucleic acids, encompassing deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) [140], are fundamental biomolecular compounds in living organisms formed by polymerizing numerous nucleotide monomers.

Nucleic acid therapies, which target genetic information in the body, have showcased potential in treating diseases. Unlike conventional therapies, which offer limited efficacy, nucleic acid approaches can ensure long-term results by suppressing, adding, replacing, or editing genes [141]. However, nucleic acid delivery alone proves inadequate when applied to cardiovascular diseases due to factors like enzymatic degradation, brief serum half-life, and cell transfection efficiency [142].

Hydrogels serve as promising delivery platforms for nucleic acid therapies. They necessitate specific chemical alterations to guarantee prolonged nucleic acid retention, stability during treatment, targeted tissue localization, and efficient cell delivery. Wei-Guo Wan et al. [79] reported cardioprotective outcomes using a hydrogel with short-hairpin RNA (shRNA) in a rat model. Yan Li et al. [118] developed an injectable hydrogel system for microRNA-21-5p, showcasing significant enhancements in key indicators and reaffirming the therapeutic potential of gene/nucleic acid therapy for myocardial infarction.

However, the current study lacks sufficient data to derive representative conclusions from the cited literature.

4.2. Multitherapy

Over the past decade, clinical insights and preliminary studies have revealed that, given the multifaceted nature and physiological intricacies of the disease, a singular treatment approach falls short of achieving optimal therapeutic outcomes [143]. Consequently, with advancements in drug delivery techniques, the pursuit of combination or Multitherapy has emerged as a promising avenue of research [143].

Adam J. Rocker et al. [20] employed a sequential delivery of three cytokines: vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), and platelet-derived growth factor (PDGF). Initially, VEGF induced angiogenesis and curbed cardiomyocyte necrosis, followed by IL-10's modulation to counteract excessive inflammation. The concluding delivery of PDGF aimed to stabilize the myocardial microenvironment and rejuvenate substantial hemodialysis. This multi-cytokine approach tailored interventions to the therapeutic demands of various pathological phases. However, while these findings hold promise, analysis indicates that the role of PDGF might be circumscribed, suggesting the need for further regimen refinements. Combining cell therapy with drug therapy has also demonstrated marked therapeutic potential. Given that the paracrine function of diverse stem cells is often not fully realized, enhancing the paracrine impact of MSCs through biomaterial integration can markedly boost therapeutic efficiency. Yang Liu et al. [86] incorporated stem cells with puerarin, which naturally scavenges ROS, thereby mitigating cardiomyocyte damage. Concurrently, when paired with puerarin, bone-derived mesenchymal stem cells bolstered the secretion of paracrine factors. A similar approach was employed by Shilan Shafei et al. [72], further underscoring the synergistic potential of such combinations.

In short, strategic therapeutic combinations can yield synergistic effects where the combined outcome surpasses the sum of individual contributions [143]. Combining multiple therapeutic agents offers advantages that outweigh the drawbacks of individual therapies, resulting in significant therapeutic benefits [144]. However, it is crucial to ensure efficient treatment while also considering biosafety [145]. The future development direction lies in establishing effective and safe combination therapy approaches that undergo repeated research validation and clinical testing.

4.3. Subgroup Analysis by Hydrogel Source

Injectable hydrogels surpass other biologic scaffold materials in fulfilling the requirements for drug delivery and cardiac implantation [146].

Numerous experimental results have demonstrated that hydrogel injections can impart specific physical, chemical, and electrical characteristics to the post-infarct myocardial area. The discussion in the present paper categorizes injectable hydrogels as those of natural origin and those chemically synthesized. Natural origin hydrogels, including collagen, fibrin, decellularized materials, chitosan, and alginate, exhibit commendable biochemical properties, bioactivity, and biocompatibility, aligning well with the in vivo implantation environment [147]. However, these naturally derived hydrogels present challenges such as inadequate mechanical attributes, consistent degradation rates, antioxidant capacities, and the required electrical conductivity for implantation [148]. A clinical trial involving alginate injectable hydrogels revealed a higher mortality rate in patients with advanced heart failure receiving hydrogel implants than those without injections, highlighting significant limitations in the clinical application of natural hydrogels [149]. Chemically synthesized hydrogels [150] (PNIPAAm-based hydrogels, Aniline-Based Materials, PEG-based hydrogels, PEG-based hydrogels) offer superior mechanical properties and stability than natural origin hydrogels [151] but often compromise biocompatibility [152]. Subgroup analyses indicated superior functional recovery with natural hydrogels, whereas chemically synthesized hydrogels excelled in morphological recovery. Hybrid hydrogels, merging the benefits of both categories, emerge as a promising avenue for future research [153].

4.4. Publication Bias and Quality Assessment

Consistent with previous research, significant publication bias was observed for both Ejection Fraction and Fractional Shortening, the primary outcomes of this analysis. Sensitivity analysis did not influence this bias. Addressing publication bias is essential for realizing genuine clinical trials using injectable hydrogels in myocardial infarction treatment. Evaluation of the SYRCLE risk of bias tool highlighted that many studies exhibited pronounced selection and implementation biases. Research methodologies for myocardial infarction animal models warrant further refinement, especially in interdisciplinary settings. Employing blinded protocols for establishing animal models, treatment allocation, and outcome measurement is imperative to ensure reliable and replicable experimental results.

The MQS analysis revealed 66 (69.5%) high-quality articles within the reviewed literature. However, a significant portion of these studies either omitted details in the randomization protocol or failed to employ blinding methods for their experiments. During data collection, literature missing primary outcome indicators was excluded, leading to the omission of some pertinent experimental studies. Future research should prioritize reporting echocardiographic parameters and morphological assessments. Such comprehensive reporting will not only ascertain the efficacy of experimental protocols but also furnish dependable results for subsequent literature reviews and inform subsequent research endeavors. As observed with the nucleic acid therapies discussed earlier, data deficiencies compromised the depth of literature analysis.

4.5. Strengths and Limitations

The meta-analysis comprised 83 papers and provided valuable insights into current research trends. However, there are certain limitations to be acknowledged. Firstly, due to challenges in modeling, the study primarily focused on murine small animal models, with limited exploration of medium and large animal models. Therefore, further large animal experiments are needed to validate the findings. Secondly, standardizing the experimental data is necessary for facilitating future analyses. Thirdly, the limited follow-up time in the existing studies hindered a comprehensive evaluation of the combined treatment's effect. It is recommended to conduct long-term follow-up assessments encompassing cardiac function, morphological indexes, and physiological parameters to provide a more valuable reference for clinical application. Lastly, publication bias was found in the main outcome indicators, which need attention.

Based on the previous systematic review and meta-analysis conducted in this article, the focus was on determining the therapeutic efficacy of injectable hydrogels compared to other types of bio-delivery scaffolds. This study further analyzed the therapeutic effectiveness of injectable hydrogels when combined with different therapies in animal models of myocardial infarction. The results revealed that combining injectable hydrogels with other therapies significantly improved the therapeutic outcomes in the ischemic myocardial region, which is crucial for restoring myocardial function and maintaining cardiac morphology. The analysis demonstrated that various combination therapy regimens successfully restored myocardial function and preserved cardiac morphology. Cellular therapy proved to have a consistently effective therapeutic effect. By carefully designing functional adaptation and action staging, the utilization of Multitherapy showed a synergistic effect, with the combined treatment producing better results than the individual therapies alone.

Analyses have indicated that the recovery of myocardial function and morphology are closely interrelated processes. However, due to the complexity of the recovery process after myocardial ischemia, individual therapies often fail to achieve efficient functional and morphological restoration. Drugs or cellular therapies alone are insufficient for the recovery of damaged myocardium. Therefore, the future direction of research lies in exploring multiple therapies. Additionally, as research on multiple therapies advances, it becomes necessary to systematically evaluate and meta-analyze combination protocols involving injectable hydrogels, which pose challenges in subdivision.

In conclusion, hydrogel-based combination therapy shows significant therapeutic effects on myocardial infarction. Based on our analysis of numerous literature sources, we advocate for comprehensive tracking of the therapeutic process and outcome measures in small animal models. Subsequently, large-scale animal experiments should be conducted to validate the actual effects. This approach will provide reliable references for clinical translation and enhance the understanding of hydrogel-based combination therapy for myocardial infarction.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study was a meta-analysis; no ethical approval was required.

CONSENT FOR PUBLICATION

AVAILABILITY OF DATA AND MATERIALS

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

FUNDING

This work is supported by the Natural Science Foundation of Tibet Autonomous Region Grant number (XZ202201ZR0036g), Tibetan University Master's Degree "High-Level Talent Cultivation Program" Project (2021-GSP-S051), and Tibet Autonomous Region Science and Technology Department central guidance for local science and technology development funds project (XZ202301YD0016C).

CONFLICT OF INTEREST

On behalf of all authors, the corresponding author states that there is no conflict of interest.

ACKNOWLEDGEMENTS

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP et al. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation. 2020;141(9):e139-e596. doi:10.1161/CIR.0000000000000757.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA et al. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol. 2018;72(18):2231-64. doi:10.1016/j.jacc.2018.08.1038.
Reed GW, Rossi JE, Cannon CP. Acute myocardial infarction. Lancet. 2017;389(10065):197-210. doi:10.1016/S0140-6736(16)30677-8.
Tariq U, Gupta M, Pathak S, Patil R, Dohare A, Misra SK. Role of Biomaterials in Cardiac Repair and Regeneration: Therapeutic Intervention for Myocardial Infarction. ACS Biomater Sci Eng. 2022;8(8):3271-98. doi:10.1021/acsbiomaterials.2c00454.
Klotz BJ, Gawlitta D, Rosenberg A, Malda J, Melchels FPW. Gelatin-Methacryloyl Hydrogels: Towards Biofabrication-Based Tissue Repair. Trends Biotechnol. 2016;34(5):394-407. doi:10.1016/j.tibtech.2016.01.002.
Pena B, Laughter M, Jett S, Rowland TJ, Taylor MRG, Mestroni L et al. Injectable Hydrogels for Cardiac Tissue Engineering. Macromol Biosci. 2018;18(6):e1800079. doi:10.1002/mabi.201800079.
Naahidi S, Jafari M, Logan M, Wang Y, Yuan Y, Bae H et al. Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. Biotechnol Adv. 2017;35(5):530-44. doi:10.1016/j.biotechadv.2017.05.006.
Wang H, Zhou J, Liu Z, Wang C. Injectable cardiac tissue engineering for the treatment of myocardial infarction. J Cell Mol Med. 2010;14(5):1044-55. doi:10.1111/j.1582-4934.2010.01046.x.
Borrelli MA, Turnquist HR, Little SR. Biologics and their delivery systems: Trends in myocardial infarction. Adv Drug Deliv Rev. 2021;173:181-215. doi:10.1016/j.addr.2021.03.014.
Rao SV, Zeymer U, Douglas PS, Al-Khalidi H, Liu J, Gibson CM et al. A randomized, double-blind, placebo-controlled trial to evaluate the safety and effectiveness of intracoronary application of a novel bioabsorbable cardiac matrix for the prevention of ventricular remodeling after large ST-segment elevation myocardial infarction: Rationale and design of the PRESERVATION I trial. Am Heart J. 2015;170(5):929-37. doi:10.1016/j.ahj.2015.08.017.
Frey N, Linke A, Suselbeck T, Muller-Ehmsen J, Vermeersch P, Schoors D et al. Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-in-man study. Circ Cardiovasc Interv. 2014;7(6):806-12. doi:10.1161/CIRCINTERVENTIONS.114.001478.
Khan K, Gasbarrino K, Mahmoud I, Dufresne L, Daskalopoulou SS, Schwertani A et al. Bioactive Scaffolds in Stem Cell-Based Therapies for Myocardial Infarction: a Systematic Review and Meta-Analysis of Preclinical Trials. Stem Cell Rev Rep. 2022;18(6):2104-36. doi:10.1007/s12015-021-10186-y.
Pilz PM, Ward JE, Chang WT, Kiss A, Bateh E, Jha A et al. Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction. Circ Res. 2022;130(12):1888-905. doi:10.1161/CIRCRESAHA.122.320246.
Diaz JH. Should Immunonutrition Become Routine in Critically Ill Patients? A Systematic Review of the Evidence. Survey of Anesthesiology. 2002;46(3):129-30.
Chen KY, Ma B, Wang YN, Chen CH, Zhao YQ, Zheng JX et al. SYRCLE's Risk of Bias Tool for Animal Studies. Chin J Evid-Based Med. 2014;14(10):1281-5.
Cochrane Handbook for Systematic Reviews of Interventions. www.training.cochrane.org/handbook.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-34. doi:10.1136/bmj.315.7109.629.
Rufaihah AJ, Vaibavi SR, Plotkin M, Shen J, Nithya V, Wang J et al. Enhanced infarct stabilization and neovascularization mediated by VEGF-loaded PEGylated fibrinogen hydrogel in a rodent myocardial infarction model. Biomaterials. 2013;34(33):8195-202. doi:10.1016/j.biomaterials.2013.07.031.
Rufaihah AJ, Johari NA, Vaibavi SR, Plotkin M, Di Thien DT, Kofidis T et al. Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel. Acta Biomater. 2017;48:58-67. doi:10.1016/j.actbio.2016.10.013.
Rocker AJ, Cavasin M, Johnson NR, Shandas R, Park D. Sulfonated Thermoresponsive Injectable Gel for Sequential Release of Therapeutic Proteins to Protect Cardiac Function after Myocardial Infarction. ACS Biomater Sci Eng. 2022;8(9):3883-98. doi:10.1021/acsbiomaterials.2c00616.
Steele AN, Cai L, Truong VN, Edwards BB, Goldstone AB, Eskandari A et al. A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function. Biotechnol Bioeng. 2017;114(10):2379-89. doi:10.1002/bit.26345.
Cohen JE, Goldstone AB, Wang H, Purcell BP, Shudo Y, MacArthur JW et al. A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model. J Cardiovasc Dev Dis. 2020;7(4). doi:10.3390/jcdd7040053.
Chow A, Stuckey DJ, Kidher E, Rocco M, Jabbour RJ, Mansfield CA et al. Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Encapsulating Bioactive Hydrogels Improve Rat Heart Function Post Myocardial Infarction. Stem Cell Reports. 2017;9(5):1415-22. doi:10.1016/j.stemcr.2017.09.003.
Gaffey AC, Chen MH, Venkataraman CM, Trubelja A, Rodell CB, Dinh PV et al. Injectable shear-thinning hydrogels used to deliver endothelial progenitor cells, enhance cell engraftment, and improve ischemic myocardium. J Thorac Cardiovasc Surg. 2015;150(5):1268-76. doi:10.1016/j.jtcvs.2015.07.035.
Waters R, Alam P, Pacelli S, Chakravarti AR, Ahmed RPH, Paul A. Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue. Acta Biomater. 2018;69:95-106. doi:10.1016/j.actbio.2017.12.025.
Paul A, Hasan A, Kindi HA, Gaharwar AK, Rao VT, Nikkhah M et al. Injectable graphene oxide/hydrogel-based angiogenic gene delivery system for vasculogenesis and cardiac repair. ACS Nano. 2014;8(8):8050-62. doi:10.1021/nn5020787.
Qian B, Yang Q, Wang M, Huang S, Jiang C, Shi H et al. Encapsulation of lyophilized platelet-rich fibrin in alginate-hyaluronic acid hydrogel as a novel vascularized substitution for myocardial infarction. Bioact Mater. 2022;7:401-11. doi:10.1016/j.bioactmat.2021.05.042.
Xu B, Li Y, Deng B, Liu X, Wang L, Zhu QL. Chitosan hydrogel improves mesenchymal stem cell transplant survival and cardiac function following myocardial infarction in rats. Exp Ther Med. 2017;13(2):588-94. doi:10.3892/etm.2017.4026.
Follin B, Ghotbi AA, Clemmensen AE, Bentsen S, Juhl M, Sondergaard RH et al. Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction. Stem Cells Int. 2018;2018:7821461. doi:10.1155/2018/7821461.
Fu B, Wang X, Chen Z, Jiang N, Guo Z, Zhang Y et al. Improved myocardial performance in infarcted rat heart by injection of disulfide-cross-linked chitosan hydrogels loaded with basic fibroblast growth factor. J Mater Chem B. 2022;10(4):656-65. doi:10.1039/d1tb01961a.
Purcell BP, Barlow SC, Perreault PE, Freeburg L, Doviak H, Jacobs J et al. Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling. Am J Physiol Heart Circ Physiol. 2018;315(4):H814-H25. doi:10.1152/ajpheart.00076.2018.
Purcell BP, Lobb D, Charati MB, Dorsey SM, Wade RJ, Zellars KN et al. Injectable and bioresponsive hydrogels for on-demand matrix metalloproteinase inhibition. Nat Mater. 2014;13(6):653-61. doi:10.1038/nmat3922.
Cimenci CE, Blackburn NJR, Sedlakova V, Pupkaite J, Munoz M, Rotstein BH et al. Combined Methylglyoxal Scavenger and Collagen Hydrogel Therapy Prevents Adverse Remodeling and Improves Cardiac Function Post‐Myocardial Infarction. Advanced Functional Materials. 2022;32(1):2108630.
Fan C, Shi J, Zhuang Y, Zhang L, Huang L, Yang W et al. Myocardial-Infarction-Responsive Smart Hydrogels Targeting Matrix Metalloproteinase for On-Demand Growth Factor Delivery. Adv Mater. 2019;31(40):e1902900. doi:10.1002/adma.201902900.
Chen CW, Wang LL, Zaman S, Gordon J, Arisi MF, Venkataraman CM et al. Sustained release of endothelial progenitor cell-derived extracellular vesicles from shear-thinning hydrogels improves angiogenesis and promotes function after myocardial infarction. Cardiovasc Res. 2018;114(7):1029-40. doi:10.1093/cvr/cvy067.
Kim CW, Kim CJ, Park E-H, Ryu S, Lee Y, Kim E et al. MSC-encapsulating in situ cross-linkable gelatin hydrogels to promote myocardial repair. ACS Applied Bio Materials. 2020;3(3):1646-55.
Chen C-H, Wang S-S, Wei EIH, Chu T-Y, Hsieh PCH. Hyaluronan enhances bone marrow cell therapy for myocardial repair after infarction. Molecular Therapy. 2013;21(3):670-9.
Chen CH, Chang MY, Wang SS, Hsieh PC. Injection of autologous bone marrow cells in hyaluronan hydrogel improves cardiac performance after infarction in pigs. Am J Physiol Heart Circ Physiol. 2014;306(7):H1078-86. doi:10.1152/ajpheart.00801.2013.
Projahn D, Simsekyilmaz S, Singh S, Kanzler I, Kramp BK, Langer M et al. Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction. Journal of cellular and molecular medicine. 2014;18(5):790-800.
Mathieu E, Lamirault G, Toquet C, Lhommet P, Rederstorff E, Sourice S et al. Intramyocardial delivery of mesenchymal stem cell-seeded hydrogel preserves cardiac function and attenuates ventricular remodeling after myocardial infarction. PloS one. 2012;7(12):e51991.
Xu G, Wang X, Deng C, Teng X, Suuronen EJ, Shen Z et al. Injectable biodegradable hybrid hydrogels based on thiolated collagen and oligo (acryloyl carbonate)–poly (ethylene glycol)–oligo (acryloyl carbonate) copolymer for functional cardiac regeneration. Acta biomaterialia. 2015;15:55-64.
Chen G, Li J, Song M, Wu Z, Zhang W, Wang Z et al. A mixed component supramolecular hydrogel to improve mice cardiac function and alleviate ventricular remodeling after acute myocardial infarction. Advanced Functional Materials. 2017;27(34):1701798.
Awada HK, Long DW, Wang Z, Hwang MP, Kim K, Wang Y. A single injection of protein-loaded coacervate-gel significantly improves cardiac function post infarction. Biomaterials. 2017;125:65-80.
Wang H, Zhang X, Li Y, Ma Y, Zhang Y, Liu Z et al. Improved myocardial performance in infarcted rat heart by co-injection of basic fibroblast growth factor with temperature-responsive chitosan hydrogel. The Journal of Heart and Lung Transplantation. 2010;29(8):881-7.
Wang H, Liu Z, Li D, Guo X, Kasper FK, Duan C et al. Injectable biodegradable hydrogels for embryonic stem cell transplantation: improved cardiac remodelling and function of myocardial infarction. Journal of cellular and molecular medicine. 2012;16(6):1310-20.
Wang H, Shi J, Wang Y, Yin Y, Wang L, Liu J et al. Promotion of cardiac differentiation of brown adipose derived stem cells by chitosan hydrogel for repair after myocardial infarction. Biomaterials. 2014;35(13):3986-98.
Ding H, Ding J, Liu Q, Lin J, He M, Wu X et al. Mesenchymal stem cells encapsulated in a reactive oxygen species-scavenging and O2-generating injectable hydrogel for myocardial infarction treatment. Chemical Engineering Journal. 2022;433:133511.
Li H, Gao J, Shang Y, Hua Y, Ye M, Yang Z et al. Folic acid derived hydrogel enhances the survival and promotes therapeutic efficacy of iPS cells for acute myocardial infarction. ACS applied materials & interfaces. 2018;10(29):24459-68.
Zhu H, Li X, Yuan M, Wan W, Hu M, Wang X et al. Intramyocardial delivery of bFGF with a biodegradable and thermosensitive hydrogel improves angiogenesis and cardio‑protection in infarcted myocardium. Experimental and therapeutic medicine. 2017;14(4):3609-15.
Cohen JE, Purcell BP, MacArthur Jr JW, Mu A, Shudo Y, Patel JB et al. A bioengineered hydrogel system enables targeted and sustained intramyocardial delivery of neuregulin, activating the cardiomyocyte cell cycle and enhancing ventricular function in a murine model of ischemic cardiomyopathy. Circulation: Heart Failure. 2014;7(4):619-26.
Ding J, Yao Y, Li J, Duan Y, Nakkala JR, Feng X et al. A reactive oxygen species scavenging and O2 generating injectable hydrogel for myocardial infarction treatment in vivo. Small. 2020;16(48):2005038.
Zhou J, Liu W, Zhao X, Xian Y, Wu W, Zhang X et al. Natural melanin/alginate hydrogels achieve cardiac repair through ROS scavenging and macrophage polarization. Advanced Science. 2021;8(20):2100505.
Chen J, Han X, Deng J, Zhang J, Li L, Ni J et al. An injectable hydrogel based on phenylboronic acid hyperbranched macromer encapsulating gold nanorods and Astragaloside IV nanodrug for myocardial infarction. Chemical Engineering Journal. 2021;413:127423.
Chen J, Guo R, Zhou Q, Wang T. Injection of composite with bone marrow-derived mesenchymal stem cells and a novel synthetic hydrogel after myocardial infarction: a protective role in left ventricle function. The Kaohsiung Journal of Medical Sciences. 2014;30(4):173-80.
Wu J, Zeng F, Huang X-P, Chung JCY, Konecny F, Weisel RD et al. Infarct stabilization and cardiac repair with a VEGF-conjugated, injectable hydrogel. Biomaterials. 2011;32(2):579-86.
Khan K, Makhoul G, Yu B, Jalani G, Derish I, Rutman AK et al. Amniotic stromal stem cell‐loaded hydrogel repairs cardiac tissue in infarcted rat hearts via paracrine mediators. Journal of Tissue Engineering and Regenerative Medicine. 2022;16(2):110-27.
Cheng K, Blusztajn A, Shen D, Li T-S, Sun B, Galang G et al. Functional performance of human cardiosphere-derived cells delivered in an in situ polymerizable hyaluronan-gelatin hydrogel. Biomaterials. 2012;33(21):5317-24.
Zhu K, Jiang D, Wang K, Zheng D, Zhu Z, Shao F et al. Conductive nanocomposite hydrogel and mesenchymal stem cells for the treatment of myocardial infarction and non-invasive monitoring via PET/CT. Journal of Nanobiotechnology. 2022;20(1):1-16.
Wu K, Wang Y, Yang H, Chen Y, Lu K, Wu Y et al. Injectable Decellularized Extracellular Matrix Hydrogel Containing Stromal Cell-Derived Factor 1 Promotes Transplanted Cardiomyocyte Engraftment and Functional Regeneration after Myocardial Infarction. ACS Applied Materials & Interfaces. 2023;15(2):2578-89.
Montazeri L, Sobat M, Kowsari‐Esfahan R, Rabbani S, Ansari H, Barekat M et al. Vascular endothelial growth factor sustained delivery augmented cell therapy outcomes of cardiac progenitor cells for myocardial infarction. Journal of Tissue Engineering and Regenerative Medicine. 2020;14(12):1939-44.
Reis LA, Chiu LLY, Wu J, Feric N, Laschinger C, Momen A et al. Hydrogels with integrin-binding angiopoietin-1–derived peptide, QHREDGS, for treatment of acute myocardial infarction. Circulation: Heart Failure. 2015;8(2):333-41.
Liu Y, Li P, Qiao C, Wu T, Sun X, Wen M et al. Chitosan hydrogel enhances the therapeutic efficacy of bone marrow–derived mesenchymal stem cells for myocardial infarction by alleviating vascular endothelial cell pyroptosis. Journal of Cardiovascular Pharmacology. 2020;75(1):75.
Vong LB, Bui TQ, Tomita T, Sakamoto H, Hiramatsu Y, Nagasaki Y. Novel angiogenesis therapeutics by redox injectable hydrogel-Regulation of local nitric oxide generation for effective cardiovascular therapy. Biomaterials. 2018;167:143-52.
Gao L, Yi M, Xing M, Li H, Zhou Y, Xu Q et al. In situ activated mesenchymal stem cells (MSCs) by bioactive hydrogels for myocardial infarction treatment. Journal of Materials Chemistry B. 2020;8(34):7713-22.
Ciuffreda MC, Malpasso G, Chokoza C, Bezuidenhout D, Goetsch KP, Mura M et al. Synthetic extracellular matrix mimic hydrogel improves efficacy of mesenchymal stromal cell therapy for ischemic cardiomyopathy. Acta Biomaterialia. 2018;70:71-83.
Chang M-Y, Huang T-T, Chen C-H, Cheng B, Hwang S-M, Hsieh PCH. Injection of human cord blood cells with hyaluronan improves postinfarction cardiac repair in pigs. Stem Cells Translational Medicine. 2016;5(1):56-66.
Chen MH, Chung JJ, Mealy JE, Zaman S, Li EC, Arisi MF et al. Injectable supramolecular hydrogel/microgel composites for therapeutic delivery. Macromolecular bioscience. 2019;19(1):1800248.
Song M, Jang H, Lee J, Kim JH, Kim SH, Sun K et al. Regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor SDF-1 and angiogenic peptide Ac-SDKP. Biomaterials. 2014;35(8):2436-45.
Qi Q, Zhu Y, Liu G, Yuan Z, Li H, Zhao Q. Local intramyocardial delivery of bioglass with alginate hydrogels for post-infarct myocardial regeneration. Biomedicine & Pharmacotherapy. 2020;129:110382.
Bao R, Tan B, Liang S, Zhang N, Wang W, Liu W. A π-π conjugation-containing soft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiac function after myocardial infarction. Biomaterials. 2017;122:63-71.
Firoozi S, Pahlavan S, Ghanian M-H, Rabbani S, Tavakol S, Barekat M et al. A cell-free SDKP-conjugated self-assembling peptide hydrogel sufficient for improvement of myocardial infarction. Biomolecules. 2020;10(2):205.
Shafei S, Khanmohammadi M, Ghanbari H, Nooshabadi VT, Tafti SHA, Rabbani S et al. Effectiveness of exosome mediated miR-126 and miR-146a delivery on cardiac tissue regeneration. Cell and Tissue Research. 2022;390(1):71-92.
Lü S, Wang H, Lu W, Liu S, Lin Q, Li D et al. Both the transplantation of somatic cell nuclear transfer-and fertilization-derived mouse embryonic stem cells with temperature-responsive chitosan hydrogel improve myocardial performance in infarcted rat hearts. Tissue Engineering Part A. 2010;16(4):1303-15.
Bao S, Lu Y, Zhang J, Xue L, Zhang Y, Wang P et al. Rapid improvement of heart repair in rats after myocardial infarction by precise magnetic stimulation on the vagus nerve with an injectable magnetic hydrogel. Nanoscale. 2023;15(7):3532-41.
Wang T, Jiang X-J, Lin T, Ren S, Li X-Y, Zhang X-Z et al. The inhibition of postinfarct ventricle remodeling without polycythaemia following local sustained intramyocardial delivery of erythropoietin within a supramolecular hydrogel. Biomaterials. 2009;30(25):4161-7.
Wang T, Jiang X-J, Tang Q-Z, Li X-Y, Lin T, Wu D-Q et al. Bone marrow stem cells implantation with α-cyclodextrin/MPEG–PCL–MPEG hydrogel improves cardiac function after myocardial infarction. Acta biomaterialia. 2009;5(8):2939-44.
Vu TD, Pal SN, Ti L-K, Martinez EC, Rufaihah AJ, Ling LH et al. An autologous platelet-rich plasma hydrogel compound restores left ventricular structure, function and ameliorates adverse remodeling in a minimally invasive large animal myocardial restoration model: a translational approach: Vu and Pal “Myocardial Repair: PRP, Hydrogel and Supplements”. Biomaterials. 2015;45:27-35.
Kraehenbuehl TP, Ferreira LS, Hayward AM, Nahrendorf M, Van Der Vlies AJ, Vasile E et al. Human embryonic stem cell-derived microvascular grafts for cardiac tissue preservation after myocardial infarction. Biomaterials. 2011;32(4):1102-9.
Wan WG, Jiang XJ, Li XY, Zhang C, Yi X, Ren S et al. Enhanced cardioprotective effects mediated by plasmid containing the short‐hairpin RNA of angiotensin converting enzyme with a biodegradable hydrogel after myocardial infarction. Journal of Biomedical Materials Research Part A. 2014;102(10):3452-8.
Wang W, Tan B, Chen J, Bao R, Zhang X, Liang S et al. An injectable conductive hydrogel encapsulating plasmid DNA-eNOs and ADSCs for treating myocardial infarction. Biomaterials. 2018;160:69-81.
Lu W-N, Lü S-H, Wang H-B, Li D-X, Duan C-M, Liu Z-Q et al. Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Engineering Part A. 2009;15(6):1437-47.
Li X, Zhou J, Liu Z, Chen J, Lü S, Sun H et al. A PNIPAAm-based thermosensitive hydrogel containing SWCNTs for stem cell transplantation in myocardial repair. Biomaterials. 2014;35(22):5679-88.
Li X-Y, Wang T, Jiang X-J, Lin T, Wu D-Q, Zhang X-Z et al. Injectable hydrogel helps bone marrow-derived mononuclear cells restore infarcted myocardium. Cardiology. 2010;115(3):194-9.
Hu X, Ning X, Zhao Q, Zhang Z, Zhang C, Xie M et al. Islet-1 mesenchymal stem cells-derived exosome-incorporated angiogenin-1 hydrogel for enhanced acute myocardial infarction therapy. ACS Applied Materials & Interfaces. 2022;14(32):36289-303.
Li Y, Chen X, Jin R, Chen L, Dang M, Cao H et al. Injectable hydrogel with MSNs/microRNA-21-5p delivery enables both immunomodification and enhanced angiogenesis for myocardial infarction therapy in pigs. Science advances. 2021;7(9):eabd6740.
Liu Y, Zhang X, Wu T, Liu B, Yang J, Liu W. Chinese herb-crosslinked hydrogel bearing rBMSCs-laden polyzwitterion microgels: Self-adaptive manipulation of micromilieu and stemness maintenance for restoring infarcted myocardium. Nano Today. 2021;41:101306.
Wu Y, Chang T, Chen W, Wang X, Li J, Chen Y et al. Release of VEGF and BMP9 from injectable alginate based composite hydrogel for treatment of myocardial infarction. Bioactive materials. 2021;6(2):520-8.
Chen Y, Li C, Li C, Chen J, Li Y, Xie H et al. Tailorable hydrogel improves retention and cardioprotection of intramyocardial transplanted mesenchymal stem cells for the treatment of acute myocardial infarction in mice. Journal of the American Heart Association. 2020;9(2):e013784.
Zhang Y, Cai Z, Shen Y, Lu Q, Gao W, Zhong X et al. Hydrogel-load exosomes derived from dendritic cells improve cardiac function via Treg cells and the polarization of macrophages following myocardial infarction. Journal of nanobiotechnology. 2021;19:1-16.
Chen Y, Shi J, Zhang Y, Miao J, Zhao Z, Jin X et al. An injectable thermosensitive hydrogel loaded with an ancient natural drug colchicine for myocardial repair after infarction. Journal of Materials Chemistry B. 2020;8(5):980-92.
Xia Y, Zhu K, Lai H, Lang M, Xiao Y, Lian S et al. Enhanced infarct myocardium repair mediated by thermosensitive copolymer hydrogel-based stem cell transplantation. Experimental Biology and Medicine. 2015;240(5):593-600.
Sakakibara Y, Nishimura K, Tambara K, Yamamoto M, Lu F, Tabata Y et al. Prevascularization with gelatin microspheres containing basic fibroblast growth factor enhances the benefits of cardiomyocyte transplantation. The Journal of thoracic and cardiovascular surgery. 2002;124(1):50-6.
Zheng Z, Guo Z, Zhong F, Wang B, Liu L, Ma W et al. A dual crosslinked hydrogel-mediated integrated peptides and BMSC therapy for myocardial regeneration. Journal of Controlled Release. 2022;347:127-42.
Zheng Z, Lei C, Liu H, Jiang M, Zhou Z, Zhao Y et al. A ROS‐Responsive Liposomal Composite Hydrogel Integrating Improved Mitochondrial Function and Pro‐Angiogenesis for Efficient Treatment of Myocardial Infarction. Advanced Healthcare Materials. 2022;11(19):2200990.
Liu Z, Wang H, Wang Y, Lin Q, Yao A, Cao F et al. The influence of chitosan hydrogel on stem cell engraftment, survival and homing in the ischemic myocardial microenvironment. Biomaterials. 2012;33(11):3093-106.
Yuan Z, Tsou Y-H, Zhang X-Q, Huang S, Yang Y, Gao M et al. Injectable citrate-based hydrogel as an angiogenic biomaterial improves cardiac repair after myocardial infarction. ACS applied materials & interfaces. 2019;11(42):38429-39.
Huang Q, Zou Y, Arno MC, Chen S, Wang T, Gao J et al. Hydrogel scaffolds for differentiation of adipose-derived stem cells. Chemical Society Reviews. 2017;46(20):6255-75.
Ma J, Huang C. Composition and mechanism of three-dimensional hydrogel system in regulating stem cell fate. Tissue Engineering Part B: Reviews. 2020;26(6):498-518.
Fan L, Liu C, Chen X, Zou Y, Zhou Z, Lin C et al. Directing induced pluripotent stem cell derived neural stem cell fate with a three-dimensional biomimetic hydrogel for spinal cord injury repair. ACS applied materials & interfaces. 2018;10(21):17742-55.
Pang Q-M, Deng K-Q, Zhang M, Wu X-C, Yang R-L, Fu S-P et al. Multiple strategies enhance the efficacy of MSCs transplantation for spinal cord injury. Biomedicine & Pharmacotherapy. 2023;157:114011.
Bhattacharjee M, Escobar Ivirico JL, Kan H-M, Shah S, Otsuka T, Bordett R et al. Injectable amnion hydrogel-mediated delivery of adipose-derived stem cells for osteoarthritis treatment. Proceedings of the National Academy of Sciences. 2022;119(4):e2120968119.
Huang J-N, Cao H, Liang K-Y, Cui L-P, Li Y. Combination therapy of hydrogel and stem cells for diabetic wound healing. World Journal of Diabetes. 2022;13(11):949.
Goldfracht I, Efraim Y, Shinnawi R, Kovalev E, Huber I, Gepstein A et al. Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications. Acta biomaterialia. 2019;92:145-59.
Hong Y, Zhou F, Hua Y, Zhang X, Ni C, Pan D et al. A strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds. Nature communications. 2019;10(1):2060.
Zhang K, Zhao X, Chen X, Wei Y, Du W, Wang Y et al. Enhanced therapeutic effects of mesenchymal stem cell-derived exosomes with an injectable hydrogel for hindlimb ischemia treatment. ACS applied materials & interfaces. 2018;10(36):30081-91.
Hwang NS, Zhang C, Hwang YS, Varghese S. Mesenchymal stem cell differentiation and roles in regenerative medicine. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2009;1(1):97-106.
Fu X, Liu G, Halim A, Ju Y, Luo Q, Song G. Mesenchymal stem cell migration and tissue repair. Cells. 2019;8(8):784.
Duran JM, Makarewich CA, Sharp TE, Starosta T, Zhu F, Hoffman NE et al. Bone-derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circulation research. 2013;113(5):539-52.
Qazi TH, Mooney DJ, Duda GN, Geissler S. Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs. Biomaterials. 2017;140:103-14.
Liu L, Gao J, Yuan Y, Chang Q, Liao Y, Lu F. Hypoxia preconditioned human adipose derived mesenchymal stem cells enhance angiogenic potential via secretion of increased VEGF and bFGF. Cell biology international. 2013;37(6):551-60.
Zhang J, Chen G-H, Wang Y-w, Zhao J, Duan H-f, Liao L-M et al. Hydrogen peroxide preconditioning enhances the therapeutic efficacy of Wharton's Jelly mesenchymal stem cells after myocardial infarction. Chinese medical journal. 2012;125(19):3472-8.
Xie X, Sun A, Zhu W, Huang Z, Hu X, Jia J et al. Transplantation of mesenchymal stem cells preconditioned with hydrogen sulfide enhances repair of myocardial infarction in rats. The Tohoku journal of experimental medicine. 2012;226(1):29-36.
Wisel S, Khan M, Kuppusamy ML, Mohan IK, Chacko SM, Rivera BK et al. Pharmacological preconditioning of mesenchymal stem cells with trimetazidine (1-[2, 3, 4-trimethoxybenzyl] piperazine) protects hypoxic cells against oxidative stress and enhances recovery of myocardial function in infarcted heart through Bcl-2 expression. Journal of Pharmacology and Experimental Therapeutics. 2009;329(2):543-50.
Yao Y, Zhang F, Wang L, Zhang G, Wang Z, Chen J et al. Lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction. Journal of biomedical science. 2009;16:1-11.
Zhang D, Fan G-C, Zhou X, Zhao T, Pasha Z, Xu M et al. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of molecular and cellular cardiology. 2008;44(2):281-92.
Tang JH-C, Titler MG. Evidence-based practice: Residency program in gerontological nursing. SLACK Incorporated Thorofare, NJ; 2003. p. 9-.
Yang Z-j, Chen B, Sheng Z, Zhang D-g, Jia E-z, Wang W et al. Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium-and high-dose groups. Molecular biology reports. 2010;37:2075-81.
Lyu Y, Xie J, Liu Y, Xiao M, Li Y, Yang J et al. Injectable hyaluronic acid hydrogel loaded with functionalized human mesenchymal stem cell aggregates for repairing infarcted myocardium. ACS Biomaterials Science & Engineering. 2020;6(12):6926-37.
Charron D, Suberbielle-Boissel C, Al-Daccak R. Immunogenicity and allogenicity: a challenge of stem cell therapy. Journal of cardiovascular translational research. 2009;2:130-8.
Silk AW, Margolin K. Cytokine Therapy. Hematol Oncol Clin North Am. 2019;33(2):261-74. doi:10.1016/j.hoc.2018.12.004.
Jarczak D, Nierhaus A. Cytokine Storm—Definition, Causes, and Implications. International journal of molecular sciences. 2022;23(19):11740.
Van Niel G, d'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nature reviews Molecular cell biology. 2018;19(4):213-28.
Xu XH, Yuan TJ, Dad HA, Shi MY, Huang YY, Jiang ZH et al. Plant Exosomes As Novel Nanoplatforms for MicroRNA Transfer Stimulate Neural Differentiation of Stem Cells In Vitro and In Vivo. Nano Lett. 2021;21(19):8151-9. doi:10.1021/acs.nanolett.1c02530.
Nagelkerke A, Ojansivu M, van der Koog L, Whittaker TE, Cunnane EM, Silva AM et al. Extracellular vesicles for tissue repair and regeneration: Evidence, challenges and opportunities. Advanced Drug Delivery Reviews. 2021;175:113775.
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.
Wang X, Chen Y, Zhao Z, Meng Q, Yu Y, Sun J et al. Engineered exosomes with ischemic myocardium‐targeting peptide for targeted therapy in myocardial infarction. Journal of the American Heart Association. 2018;7(15):e008737.
Lin J, Li J, Huang B, Liu J, Chen X, Chen X-M et al. Exosomes: novel biomarkers for clinical diagnosis. The scientific world journal. 2015;2015.
Gao X, Ran N, Dong X, Zuo B, Yang R, Zhou Q et al. Anchor peptide captures, targets, and loads exosomes of diverse origins for diagnostics and therapy. Science translational medicine. 2018;10(444):eaat0195.
Wang C, Li Z, Liu Y, Yuan L. Exosomes in atherosclerosis: performers, bystanders, biomarkers, and therapeutic targets. Theranostics. 2021; 11 (8): 3996–4010.
Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. Journal of molecular and cellular cardiology. 2011;50(2):280-9.
Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation research. 2006;98(11):1414-21.
Die Pharmazie - An International Journal of Pharmaceutical Sciences. https://www.ingentaconnect.com/content/govi/pharmaz.
Li H, Sureda A, Devkota HP, Pittalà V, Barreca D, Silva AS et al. Curcumin, the golden spice in treating cardiovascular diseases. Biotechnology advances. 2020;38:107343.
Le Thi P, Tran DL, Hoang Thi TT, Lee Y, Park KD. Injectable reactive oxygen and nitrogen species-controlling hydrogels for tissue regeneration: current status and future perspectives. Regenerative Biomaterials. 2022;9:rbac069.
Yang C, Zhu C, Li Y, Li Z, Zhang Z, Xu J et al. Injectable selenium-containing polymeric hydrogel formulation for effective treatment of myocardial infarction. Frontiers in Bioengineering and Biotechnology. 2022;10:912562.
Du G, Sun L, Zhao R, Du L, Song J, Zhang L et al. Polyphenols: Potential source of drugs for the treatment of ischaemic heart disease. Pharmacology & therapeutics. 2016;162:23-34.
Baumann MD, Kang CE, Stanwick JC, Wang Y, Kim H, Lapitsky Y et al. An injectable drug delivery platform for sustained combination therapy. Journal of Controlled Release. 2009;138(3):205-13.
Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nature biotechnology. 2015;33(9):941-51.
Hasan A, Khattab A, Islam MA, Hweij KA, Zeitouny J, Waters R et al. Injectable hydrogels for cardiac tissue repair after myocardial infarction. Advanced Science. 2015;2(11):1500122.
Singh RP, Srivastava AK, Yang Y-J, Manchanda G, Kumar A, Yerpude ST et al. Nucleic acid nanotechnology: Trends, opportunities and challenges. Current Pharmaceutical Biotechnology. 2023;24(1):50-60.
Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR et al. The current landscape of nucleic acid therapeutics. Nature nanotechnology. 2021;16(6):630-43.
Mo F, Jiang K, Zhao D, Wang Y, Song J, Tan W. DNA hydrogel-based gene editing and drug delivery systems. Advanced Drug Delivery Reviews. 2021;168:79-98.
Poustchi F, Amani H, Ahmadian Z, Niknezhad SV, Mehrabi S, Santos HA et al. Combination therapy of killing diseases by injectable hydrogels: from concept to medical applications. Advanced healthcare materials. 2021;10(3):2001571.
Almawash S, Osman SK, Mustafa G, El Hamd MA. Current and future prospective of injectable hydrogels—design challenges and limitations. Pharmaceuticals. 2022;15(3):371.
Vashist A, Kaushik A, Alexis K, Dev Jayant R, Sagar V, Vashist A et al. Bioresponsive injectable hydrogels for on-demand drug release and tissue engineering. Current pharmaceutical design. 2017;23(24):3595-602.
Han X, Alu A, Liu H, Shi Y, Wei X, Cai L et al. Biomaterial-assisted biotherapy: A brief review of biomaterials used in drug delivery, vaccine development, gene therapy, and stem cell therapy. Bioactive Materials. 2022;17:29-48.
Catoira MC, Fusaro L, Di Francesco D, Ramella M, Boccafoschi F. Overview of natural hydrogels for regenerative medicine applications. J Mater Sci Mater Med. 2019;30(10):115. doi:10.1007/s10856-019-6318-7.
Xia B, Chen G. Research progress of natural tissue-derived hydrogels for tissue repair and reconstruction. International Journal of Biological Macromolecules. 2022;214:480-91.
Anker SD, Coats AJS, Cristian G, Dragomir D, Pusineri E, Piredda M et al. A prospective comparison of alginate-hydrogel with standard medical therapy to determine impact on functional capacity and clinical outcomes in patients with advanced heart failure (AUGMENT-HF trial). European heart journal. 2015;36(34):2297-309.
Peters JT, Wechsler ME, Peppas NA. Advanced biomedical hydrogels: molecular architecture and its impact on medical applications. Regenerative Biomaterials. 2021;8(6):rbab060.
Gomez-Florit M, Pardo A, Domingues RMA, Graca AL, Babo PS, Reis RL et al. Natural-Based Hydrogels for Tissue Engineering Applications. Molecules. 2020;25(24). doi:10.3390/molecules25245858.
Wang S, Ong PJ, Liu S, Thitsartarn W, Tan MJBH, Suwardi A et al. Recent Advances in Host‐Guest Supramolecular Hydrogels for Biomedical Applications. Chemistry–An Asian Journal. 2022;17(18):e202200608.
Neves SC, Moroni L, Barrias CC, Granja PL. Leveling up hydrogels: hybrid systems in tissue engineering. Trends in biotechnology. 2020;38(3):292-315.

No competing interests reported.

Download PDF

Journal Publication

published 21 Feb, 2024

Read the published version in BMC Cardiovascular Disorders →

Editorial decision: Revision requested
05 Nov, 2023
Reviews received at journal
27 Oct, 2023
Reviewers agreed at journal
12 Oct, 2023
Reviewers invited by journal
11 Oct, 2023
Editor assigned by journal
11 Oct, 2023
Editor invited by journal
05 Oct, 2023
Submission checks completed at journal
05 Oct, 2023
First submitted to journal
30 Sep, 2023

You are reading this latest preprint version

Injectable Hydrogel-Based Combination Therapy for Myocardial Infarction: A Systematic Review and Meta-Analysis of Preclinical Trials

Status:

Journal Publication

Version 1

Abstract

Figures

1. INTRODUCTION

2. MATERIALS AND METHODS

2.1. Protocols and Registration

2.2. Search Strategy and Data Sources

2.3. Study Eligibility

2.4. Data Extraction

2.5. Statistical Analysis

3. RESULTS

3.1. Search Results

3.2. Study Characteristic

3.3. Quality and Risk of Bias Assessment

3.4. Effect of Injectable Hydrogel Combination Therapy on Cardiac Function

3.5. Subgroup Analysis

3.6. Publication Bias

4. DISCUSSION

4.1. Monotherapy

4.1.1. Cellular therapy

4.1.2. Cytokine therapy

4.1.3. Extracellular vesicle therapy

4.1.4. Drug therapy

4.1.5. Nucleic acid therapy

4.2. Multitherapy

4.3. Subgroup Analysis by Hydrogel Source

4.4. Publication Bias and Quality Assessment

4.5. Strengths and Limitations

CONCLUSION

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1