Therapeutic Hydrogel Research Articles

Injectable Extracellular Matrix Microparticles Promote Heart Regeneration in Mice with Post-ischemic Heart Injury.

Ischemic heart injury causes permanent cardiomyocyte loss and fibrosis impairing cardiac function. Tissue derived biomaterials have shown promise as an injectable treatment for the post-ischemic heart. Specifically, decellularized extracellular matrix (dECM) is a protein rich suspension that forms a therapeutic hydrogel once injected and improves the heart post-injury response in rodents and pig models. Current dECM-derived biomaterials are delivered to the heart as a liquid dECM hydrogel precursor or colloidal suspension, which gels over several minutes. To increase the functionality of the dECM therapy, an injectable solid dECM microparticle formulation derived from heart tissue to control sizing and extend stability in aqueous conditions is developed. When delivered into the infarcted mouse heart, these dECM microparticles protect cardiac function promote vessel density and reduce left ventricular remodeling by sustained delivery of biomolecules. Longer retention, higher stiffness, and slower protein release of dECM microparticles are noted compared to liquid dECM hydrogel precursor. In addition, the dECM microparticle can be developed as a platform for macromolecule delivery. Together, the results suggest that dECM microparticles can be developed as a modular therapy for heart injury.

A Logic-Based Diagnostic and Therapeutic Hydrogel with Multistimuli Responsiveness to Orchestrate Diabetic Bone Regeneration.

The regeneration of diabetic bone defects remains challenging as the innate healing process is impaired by glucose fluctuation, reactive oxygen species (ROS), and overexpression of proteinases (such as matrix metalloproteinases, MMPs). A "diagnostic" and therapeutic dual-logic-based hydrogel for diabetic bone regeneration is therefore developed through the design of a double-network hydrogel consisting of phenylboronic-acid-crosslinked poly(vinyl alcohol) and gelatin colloids. It exhibits a "diagnostic" logic to interpret pathological cues (glucose fluctuation, ROS, MMPs) and determines when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration. The hydrogel is also shown to be mechanically adaptable to the local complexity at the bone defect. Furthermore, the underlying therapeutic mechanism is elucidated, whereby the logic-based cargo release enables the regulation of macrophage polarization by remodeling the mitochondria-related antioxidative system, resulting in enhanced osteogenesis in diabetic bone defects. This study provides critical insight into the design and biological mechanism of dual-logic-based tissue-engineering strategies for diabetic bone regeneration.

Fabrication of injectable hydrogels from an anticancer peptide for local therapeutic delivery and synergistic photothermal-chemotherapy.

The susceptibility of anticancer peptides to proteolytic degradation is often considered as a major weakness that limits systemic therapeutic applications. However, localized delivery of anticancer peptides via injectable hydrogels is expected to improve drug efficacy and reduce systemic toxicity. Herein, an injectable hydrogel with drug releasing properties, NIR responsiveness and pH sensitivity was developed from an anticancer peptide (KL), Fe3+ ions and protocatechualdehyde via dynamic and reversible interactions. Benefiting from the formation of Fe(III)-catechol complexes between Fe3+ ions and protocatechualdehyde within gel networks, the obtained hydrogel exhibited intrinsic NIR absorption properties for photothermal ablation of tumor cells, and remote light control of drug release. Besides, the pH-labile imine bonds between KL and protocatechualdehyde endowed the injectable gel with pH sensitivity for sustained release of KL under a mildly acidic environment, inducing membrane destabilization and facilitating the cell uptake of DOX for combinational chemotherapy. Both in vitro and in vivo experiments revealed that the injectable hydrogel exhibited a synergistic therapeutic effect on inhibiting tumor growth via combinational photothermal-chemotherapy. Therefore, this work provides a promising attempt to develop a therapeutic hydrogel from an anticancer peptide, which could work as a localized drug delivery platform for synergistic photothermal-chemotherapy.

ROS-Scavenging Therapeutic Hydrogels for Modulation of the Inflammatory Response.

Although reactive oxygen species (ROS) are essential for cellular processes, excessive ROS could be a major cause of various inflammatory diseases because of the oxidation of proteins, DNA, and membrane lipids. It has recently been suggested that the amount of ROS could thus be regulated to treat such physiological disorders. A ROS-scavenging hydrogel is a promising candidate for therapeutic applications because of its high biocompatibility, 3D matrix, and ability to be modified. Approaches to conferring antioxidant properties to normal hydrogels include embedding ROS-scavenging catalytic nanoparticles, modifying hydrogel polymer chains with ROS-adsorbing organic moieties, and incorporating ROS-labile linkers in polymer backbones. Such therapeutic hydrogels can be used for wound healing, cardiovascular diseases, bone repair, ocular diseases, and neurodegenerative disorders. ROS-scavenging hydrogels could eliminate oxidative stress, accelerate the regeneration process, and show synergetic effects with other drugs or therapeutic molecules. In this review, the mechanisms by which ROS are generated and scavenged in the body are outlined, and the effects of high levels of ROS and the resulting oxidative stress on inflammatory diseases are described. Next, the mechanism of ROS scavenging by hydrogels is explained depending on the ROS-scavenging agents embedded within the hydrogel. Lastly, the recent achievements in the development of ROS-scavenging hydrogels to treat various inflammation-associated diseases are presented.

Design Strategy for a Hydroxide-Triggered pH-Responsive Hydrogel as a Mucoadhesive Barrier to Prevent Metabolism Disorders

Excess nutrient uptake is one of the main factors of complications related to metabolism disorders. Therefore, efforts have emerged to modulate nutrient transport in the intestine. However, current approaches are mainly invasive interventions with various side effects. Here, a pH-responsive hydrogel is formulated by acidifying the hydroxide compounds within sucralfate to allow electrostatic interactions between pectin and aluminum ions. The pH responsiveness relies on the alternation of cations and hydroxide species, providing reversible shifting from a hydrogel to a complex coacervate system. It acts as a transient physical barrier coating to inhibit intestinal absorption and changes the viscosity and barrier function in different parts of the gastrointestinal tract, showing enhanced mucoadhesive properties. The therapeutic hydrogel remarkably lowers the immediate blood glucose response by modulating nutrient contact with bowel mucosa, suggesting potential in treating diabetes. In addition, it significantly reduces weight gain, fat accumulation, and hepatic lipid deposition in rodent models. This study provides a novel strategy for fabricating pH-responsive hydrogels, which may serve as a competent candidate for metabolism disorder management.

A Sequential Therapeutic Hydrogel With Injectability and Antibacterial Activity for Deep Burn Wounds' Cleaning and Healing.

As a severe clinical challenge, escharotomy and infection are always the core concerns of deep burn injuries. However, a usual dressing without multifunctionality leads to intractable treatment on deep burn wounds. Herein, we fabricated a sequential therapeutic hydrogel to solve this problem. Cross-linked by modified polyvinyl alcohol (PVA-SH/ε-PL) and benzaldehyde-terminated F127 triblock copolymers (PF127-CHO), the hydrogel demonstrated excellent mechanical properties, injectability, tissue adhesiveness, antibacterial activity, biocompatibility, and satisfactory wound cleaning through both in vitro and in vivo assays. Additionally, based on the conception of “sequential therapy,” we proposed for the first time to load bromelain and EGF into the same hydrogel in stages for wound cleaning and healing. This work provides a strategy to fabricate a promising wound dressing for the treatment of deep burn wounds with injectability and improved patients’ compliance as it simplified the process of treatment due to its “three in one” characteristic (antibacterial activity, wound cleaning, and healing effects); therefore, it has great potential in wound dressing development and clinical application.

Evaluation of Therapeutic Collagen-Based Biomaterials in the Infarcted Mouse Heart by Extracellular Matrix Targeted MALDI Imaging Mass Spectrometry.

The goal of this study was to develop strategies to localize human collagen-based hydrogels within an infarcted mouse heart, as well as analyze its impact on endogenous extracellular matrix (ECM) remodeling. Collagen is a natural polymer that is abundantly used in bioengineered hydrogels because of its biocompatibility, cell permeability, and biodegradability. However, without the use of tagging techniques, collagen peptides derived from hydrogels can be difficult to differentiate from the endogenous ECM within tissues. Imaging mass spectrometry is a robust tool capable of visualizing synthetic and natural polymeric molecular structures yet is largely underutilized in the field of biomaterials outside of surface characterization. In this study, our group leveraged a recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) technique to enzymatically target collagen and other ECM peptides within the tissue microenvironment that are both endogenous and hydrogel-derived. Using a multimodal approach of fluorescence microscopy and ECM-IMS techniques, we were able to visualize and relatively quantify significantly abundant collagen peptides in an infarcted mouse heart that were localized to regions of therapeutic hydrogel injection sites. On-tissue MALDI MS/MS was used to putatively identify sites of collagen peptide hydroxyproline site occupancy, a post-translational modification that is critical in collagen triple helical stability. Additionally, the technique could putatively identify over 35 endogenously expressed ECM peptides that were expressed in hydrogel-injected mouse hearts. Our findings show evidence for the use of MALDI-IMS in assessing the therapeutic application of collagen-based biomaterials.

RNA-packed hydrogel treats cancer in mice

A therapeutic hydrogel that can be injected or sprayed onto large surfaces could be an effective tool in fighting cancers that grow on organ surfaces and the linings of body cavities ( Nat. Nanotechnol . 2021, DOI: 10.1038/s41565-021-00961-w ). Cancers like mesothelioma are hard for surgeons to remove completely. “You always leave residual cancer behind, so there is always a recurrence,” says Joel P. Schneider, an organic chemist and deputy director of the Center for Cancer Research at the National Cancer Institute. A therapy applied to tissue during removal surgery to combat that residual cancer “could be a game changer,” he says. Schneider, thoracic surgical oncologist Chuong D. Hoang, and their colleagues based their therapy on microRNA (miRNA), small bits of ribonucleic acids that regulate protein formation. These sequences can suppress the production of cancer proteins. The challenge has been delivering miRNA. Its strong negative charge keeps it from getting

Therapeutic hydrogel sheets programmed with multistage drug delivery for effective treatment of corneal abrasion

Corneal abrasion (CA) is a leading cause of inflammation, scar formation, and even loss of vision in the eye if allowed to progress; however, current treatments remain constrained by complex and sequential conditions that impede access to most therapies for progressively abraded corneas. Herein, an advanced therapeutic hydrogel sheet (THS) constructed via electrostatic assembly of a functional hydrogel and a ternary drug-carrier system is reported. Specifically, the functional hydrogel comprises a poly(hydroxyethyl methacrylate), a positively charged chitosan, and zinc oxide nanoparticles. The ternary drug-carrier system is composed of dipalmitoylphosphatidylcholine liposome (DPPC) nanoparticles containing epigallocatechin gallate (EGCG) and hyaluronic acid nanoparticles with low and high crosslinking degrees, which separately carrying β-1,3-glucan and SB431542. Owing to the tailored degradability of the ternary system, the THS is able to provide multistage drug release, consequently allowing successive drug administration onto an ocular surface afflicted with CA for the suppression of inflammatory response in the early stage (by the fastest released EGCG) of corneal tissue repair, followed by promotion of wound healing in the middle stage (the moderately fast released β-1,3-glucan) and prevention of scar formation in the final stage (by the slowest released SB431542). In a rabbit model of CA, the THS has a significant treatment efficacy for repairing injured cornea tissues and demonstrates a percent recovery of greater than 90%, which represents a more than eight-fold improvement compared to conventional eye drops. The therapeutic hydrogel material demonstrated here can adapt to a variety of drug molecules, opening up a new avenue for the treatment of complex ocular diseases.

Applications of Functionalized Hydrogels in the Regeneration of the Intervertebral Disc

Intervertebral disc degeneration (IDD) is caused by genetics, aging, and environmental factors and is one of the leading causes of low back pain. The treatment of IDD presents many challenges. Hydrogels are biomaterials that possess properties similar to those of the natural extracellular matrix and have significant potential in the field of regenerative medicine. Hydrogels with various functional qualities have recently been used to repair and regenerate diseased intervertebral discs. Here, we review the mechanisms of intervertebral disc homeostasis and degeneration and then discuss the applications of hydrogel-mediated repair and intervertebral disc regeneration. The classification of artificial hydrogels and natural hydrogels is then briefly introduced, followed by an update on the development of functional hydrogels, which include noncellular therapeutic hydrogels, cellular therapeutic hydrogel scaffolds, responsive hydrogels, and multifunctional hydrogels. The challenges faced and future developments of the hydrogels used in IDD are discussed as they further promote their clinical translation.

A tunable self-healing ionic hydrogel with microscopic homogeneous conductivity as a cardiac patch for myocardial infarction repair

Conductive hydrogel is a potential therapeutic tool to treat damaged heart muscles in myocardial infarction (MI). However, it is still a quite challenge to optimize the fabrication of a therapeutic hydrogel patch that sustains favorable biocompatibility, electronic and mechanical stability under a complicated MI microenvironment. Herein, a tunable self-healing ionic hydrogel (POG1) was developed through the introduction of a biocompatible polyacrylic acid (PAA, FDA-approved) into the hydrogel matrix. The fabricated POG1 hydrogel possessed suitable stretchable (>500% strain) and compressive (>85% strain) properties, comparable modulus with mammalian heart (30–500 kPa, Young's modulus), self-healable, and highly stable conductivity during large deformations (~50% compress strain, ~150% tensile strain). Specifically, the established PAA nano-channels inside of POG1 endowed the hydrogel with microscopic ultra-homogeneous conductivity. Compared to those seeded in the electronic conductors-embedded (PPy, CNT, rGO) hydrogels, the cardiomyocytes (CMs) seeded in the POG1 hydrogel exhibited more significantly oriented sarcomeres. This POG1 engineered cardiac patch (ECP) also exerted robust benefits in attenuating left ventricular remodeling and restoring heart function after implantation in vivo. This paper highlighted a previously unexplored strategy for a biocompatible ionic conductive hydrogel ECP with an excellent MI repair function.

Therapeutic Hydrogel Lenses and the Antibacterial and Antibiotic Drugs Release

The aim of this research was to evaluate the effects of different lens types on the availability and efficacy of anti-inflammatory and antibiotic drugs. Three lens types were examined: (1) nonionic hydrogel lenses; (2) ionic hydrogel lenses; and (3) silicone hydrogel lenses. The lenses were incubated with (a) dexamethasone; (b) betamethasone; (c) bromophenacyl bromide; and (d) chloramphenicol. Drug availability was quantified by gradient HPLC, and chloramphenicol antibacterial activity was quantified by testing the inhibition of Salmonella typhimurium growth on agar. The lens allowing the most abundant passage of betamethasone was the ionic hydrogel lens, followed by the silicone hydrogel lens and nonionic hydrogel lens. The lens allowing the most abundant passage of dexamethasone was the ionic hydrogel lens, but only at 0.5 h and 1 h. Regarding chloramphenicol, the ionic hydrogel lens and silicone hydrogel lens allowed more abundant passage than the nonionic hydrogel lens. These results highlight the relevance of adapting lenses to anti-inflammatory therapy, thus allowing a personalized medical approach.

PH-Responsive Charge-Conversion Progelator Peptides.

A simple strategy for generating stimuli-responsive peptide-based hydrogels via charge-conversion of a self-assembling peptide (SAP) is described. These materials are formulated as soluble, polyanionic peptides, containing maleic acid, citraconic acid, or dimethylmaleic acid masking groups on each lysine residue, which do not form assemblies, but instead flow easily through high gauge needles and catheters. Acid-induced mask hydrolysis renews the zwitterionic nature of the peptides with concomitant and rapid self-assembly via β-sheet formation into rehealable hydrogels. The use of different masks enables one to tune pH responsiveness and assembly kinetics. In anticipation of their potential for in vivo hydrogel delivery and use, progelators exhibit hemocompatibility in whole human blood, and their peptide components are shown to be noncytotoxic. Finally, demonstration of stimuli-induced self-assembly for dye sequestration suggests a simple, non-covalent strategy for small molecule encapsulation in a degradable scaffold. In summary, this simple, scalable masking strategy allows for preparation of responsive, dynamic self-assembling biomaterials. This work sets the stage for implementing biodegradable therapeutic hydrogels that assemble in response to physiological, disease-relevant states of acidosis.

An in vitro 3D diabetic human skin model from diabetic primary cells

Diabetes mellitus, a complex metabolic disorder, leads to many health complications like kidney failure, diabetic heart disease, stroke, and foot ulcers. Treatment approaches of diabetes and identification of the mechanisms underlying diabetic complications of the skin have gained importance due to continued rapid increase in the diabetes incidence. A thick and pre-vascularized in vitro 3D type 2 diabetic human skin model (DHSM) was developed in this study. The methacrylated gelatin (GelMA) hydrogel was produced by photocrosslinking and its pore size (54.85 ± 8.58 μm), compressive modulus (4.53 ± 0.67 kPa) and swelling ratio (17.5 ± 2.2%) were found to be suitable for skin tissue engineering. 8% GelMA hydrogel effectively supported the viability, spreading and proliferation of human dermal fibroblasts. By isolating dermal fibroblasts, human umbilical vein endothelial cells and keratinocytes from type 2 diabetic patients, an in vitro 3D type 2 DHSM, 12 mm in width and 1.86 mm thick, was constructed. The skin model consisted of a continuous basal epidermal layer and a dermal layer with blood capillary-like structures, ideal for evaluating the effects of anti-diabetic drugs and wound healing materials and factors. The functionality of the DHSM was showed by applying a therapeutic hydrogel into its central wound; especially fibroblast migration to the wound site was evident in 9 d. We have demonstrated that DHSM is a biologically relevant model with sensitivity and predictability in evaluating the diabetic wound healing potential of a therapeutic material.

Polydeoxyribonucleotide-delivering therapeutic hydrogel for diabetic wound healing

Patients with diabetes experience delayed wound healing because of the uncontrolled glucose level in their bloodstream, which leads to impaired function of white blood cells, poor circulation, decreased production and repair of new blood vessels. Treatment using polydeoxyribonucleotide (PDRN), which is a DNA extracted from the sperm cells of salmon, has been introduced to accelerate the healing process of diabetic wounds. To accelerate the wound-healing process, sustained delivery of PDRN is critical. In this study, taking advantage of the non-invasive gelation property of alginate, PDRN was loaded inside the hydrogel (Alg-PDRN). The release behavior of PDRN was altered by controlling the crosslinking density of the Alg hydrogel. The amount of PDRN was the greatest inside the hydrogel with the highest crosslinking density because of the decreased diffusion. However, there was an optimal degree of crosslinking for the effective release of PDRN. In vitro studies using human dermal fibroblasts and diabetes mellitus fibroblasts and an in ovo chorioallantoic membrane assay confirmed that the Alg-PDRN hydrogel effectively induced cell proliferation and expression of angiogenic growth factors and promoted new blood vessel formation. Its effectiveness for accelerated diabetic wound healing was also confirmed in an in-vivo animal experiment using a diabetic mouse model.

Injectable biodegradation-visual self-healing citrate hydrogel with high tissue penetration for microenvironment-responsive degradation and local tumor therapy

Local tumor therapy through injectable biodegradable hydrogels with controlled drug release has attracted much attention recently, due to their easy operation, low side effect and efficiency. However, most of the reported therapeutic hydrogel system showed a lack of biodegradation tracking and tumor environment-responsive degradation/therapy. Herein, we developed a multifunctional injectable biodegradation-visual citric acid-based self-healing scaffolds with microenvironment-responsive degradation and drug release for safe and efficient skin tumor therapy (FPRC hydrogel). FPRC scaffolds possess multifunctional properties including thermosensitive, injectable, self-healing, photoluminescent and pH-responsive degradation/drug release. The FPRC scaffolds with strong red fluorescence which has good photostability, tissue penetration and biocompatibility can be tracked and monitored to evaluate the degradation of the scaffolds in vivo. Moreover, the FPRC scaffolds showed pH-responsive doxorubicin (DOX) release, efficiently killed the A375 cancer cell in vitro and suppressed the tumor growth in vivo. Compared to the free drug (DOX), the FPRC@DOX scaffolds displayed a significantly high therapeutic effect and less biotoxicity. This work provides an alternative strategy to design smart visual scaffolds for tumor therapy and regenerative medicine.

Chitosan Hydrogels for Synergistic Delivery of Chemotherapeutics to Triple Negative Breast Cancer Cells and Spheroids.

This study aimed to develop a hydrogel system for treating aggressive triple negative breast cancer (TNBC) via kinetically-controlled delivery of the synergistic drug pair doxorubicin (DOX) and gemcitabine (GEM). A 2D assay was adopted to evaluate therapeutic efficacy by determining combination index (CI), and a 3D assay using cancer spheroids was implemented to assess the potential for translation in vivo. The release of DOX and GEM from an acetylated-chitosan (ACS, degree of acetylation χAc = 40 ± 5%) was characterized to identify a combined drug loading that affords release kinetics and dose that are therapeutically synergistic. The selected DOX/GEM-ACS formulation was evaluated in vitro with 2-D and 3-D models of TNBC to determine the combination index (CI) and the tumor volume reduction, respectively. Therapeutically desired release dosages and kinetics of GEM and DOX were achieved. When evaluated with a 2-D model of TNBC, the hydrogel afforded a CI of 0.14, indicating a stronger synergism than concurrent administration of DOX and GEM (CI = 0.23). Finally, the therapeutic hydrogel accomplished a notable volume reduction of the cancer spheroids (up to 30%), whereas the corresponding dosages of free drugs only reduced growth rate. The ACS hydrogel delivery system accomplishes drug release kinetics and molar ratio that affords strong therapeutically synergism. These results, in combination with the choice of ACS as affordable and highly abundant source material, provide a strong pre-clinical demonstration of the potential of the proposed system for complementing surgical resection of aggressive solid tumors.

The synthesizing of different hydrogel nanocarriers for oral insulin delivery

Diabetes is seen as the global health problem of the world due to the high risk of complications and the increasing prevalence of death. The routine diagnosis of diabetes is the injection of insulin. This treatment has a lot of side effects known to the patient (infection at injection sites, irritation, etc.). In order to overcome such conditions in the treatment of diabetes and provide faster recovery, many different delivery systems for insulin are being studied. Hydrogels are interesting polymers with hydrophobic structure that can be designed in 3D networks for oral insulin delivery. In this study, we studied the synthesis of biodegradable, biocompatible, low-toxicity therapeutic hydrogels. Acrylamide (ACR):carboxymethyl cellulose (CMC) (ACR/CMC), Acrylamide (ACR): Chitosan (Chi) and Chitosan:glutaraldehyde hydrogels were prepared. The CMC was used in acrylamide-based hydrogels for both comonomer and biocompatibility. The swelling capacity of hydrogels and the in vitro release of insulin from hydrogels were studied at different pH. Insulin release studies have shown that ACR/CMC hydrogels are a good and new alternative as an oral insulin carrier.

Nanoparticle-Loaded Hydrogel for the Light-Activated Release and Photothermal Enhancement of Antimicrobial Peptides.

Rising concerns over multidrug-resistant bacteria have necessitated an expansion to the current antimicrobial arsenal and forced the development of novel delivery strategies that enhance the efficacy of existing treatments. Antimicrobial peptides (AMPs) are a promising antibiotic alternative that physically disrupts the membrane of bacteria, resulting in rapid bactericidal activity; however, clinical translation of AMPs has been hindered by their susceptibility to protease degradation. Through the co-loading of liposomes encapsulating model AMP, IRIKIRIK-CONH2 (IK8), and gold nanorods (AuNRs) into a poly(ethylene glycol) (PEG) hydrogel, we have demonstrated the ability to protect encapsulated materials from proteolysis and provide the first instance of the triggered AMP release. Laser irradiation at 860 nm, at 2.1 W cm-2, for 10 min led to the photothermal triggered release of IK8, resulting in bactericidal activity against Gram-negative Pseudonomas aeruginosa and Gram-positive Staphylococcus aureus. Furthermore, by increasing the laser intensity to 2.4 W cm-2, we have shown the thermal enhancement of AMP activity. The photothermal triggered release, and enhancement of AMP efficacy, was demonstrated to treat two rounds of fresh S. aureus, indicating that the therapeutic gel has the potential for multiple rounds of treatment. Taken together, this novel therapeutic hydrogel system demonstrates the stimuli-responsive release of AMPs with photothermal enhanced antimicrobial efficacy to treat pathogenic bacteria.

Radio-metal cross-linking of alginate hydrogels for non-invasive in vivo imaging

Alginate hydrogels are cross-linked polymers with high water content, tuneable chemical and material properties, and a range of biomedical applications including drug delivery, tissue engineering, and cell therapy. However, their similarity to soft tissue often renders them undetectable within the body using conventional bio-medical imaging techniques. This leaves much unknown about their behaviour in vivo, posing a challenge to therapy development and validation.To address this, we report a novel, fast, and simple method of incorporating the nuclear imaging radio-metal 111In into the structure of alginate hydrogels by utilising its previously-undescribed capacity as an ionic cross-linking agent. This enabled non-invasive in vivo nuclear imaging of hydrogel delivery and retention across the whole body, over time, and across a range of model therapies including: nasal and oral drug delivery, stem cell transplantation, and cardiac tissue engineering. This information will facilitate the development of novel therapeutic hydrogel formulations, encompassing alginate, across disease categories.