Polymer-nanoparticle Hydrogel Research Articles

Modular and Photoreversible Polymer-Nanoparticle Hydrogels via Host-Guest Interactions.

Polymer-nanoparticle (PNP) hydrogels are a class of nanocomposite materials showing potential as injectable platforms for biomedical applications. Their design is limited by incomplete knowledge of how the binding motif impacts the viscoelastic properties of the material and is generally constrained to non-responsive supramolecular interactions. Expanding the scope of available interactions and advancing the understanding of how defined interactions influence network formation would accelerate PNP hydrogel design. To address this gap in the design of PNP hydrogels, the study designs and investigates a tunable platform based on beta-cyclodextrin (βCD) host-guest cross-links between functionalized polymers and nanoparticles. A host-functionalized polymer (βCD hyaluronic acid) and guest harboring block co-polymer (poly(ethylene glycol)-b-poly(lactic acid)) NPs are synthesized. The presence and accessibility for binding of the host and guest moieties are characterized via isothermal titration calorimetry. PNP hydrogels with varying concentrations of functionalized polymer and NPs reveal a limited window of concentrations for gelation. It is hypothesized that network formation is governed by the capacity of polymer chains to effectively bridge NPs, which is related to the host-guest ratios present in the system. Further, photo-responsive guests are incorporated to engineer photoreversible gelation of PNP hydrogels via exposure to specific wavelengths of light.

Generation of an inflammatory niche in an injectable hydrogel depot through recruitment of key immune cells improves efficacy of mRNA vaccines.

Messenger RNA (mRNA) delivered in lipid nanoparticles (LNPs) rose to the forefront of vaccine candidates during the COVID-19 pandemic due in part to scalability, adaptability, and potency. Yet there remain critical areas for improvements of these vaccines in durability and breadth of humoral responses. In this work, we explore a modular strategy to target mRNA/LNPs to antigen presenting cells with an injectable polymer-nanoparticle (PNP) hydrogel depot technology which recruits key immune cells and forms an immunological niche in vivo. We characterize this niche on a single cell level and find it is highly tunable through incorporation of adjuvants like MPLAs and 3M-052. Delivering commercially available SARS-CoV-2 mRNA vaccines in PNP hydrogels improves the durability and quality of germinal center reactions, and the magnitude, breadth, and durability of humoral responses. The tunable immune niche formed within PNP hydrogels effectively skews immune responses based on encapsulated adjuvants, creating opportunities to precisely modulate mRNA/LNP vaccines for various indications from infectious diseases to cancers.

Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS-CoV-2 Subunit Vaccine.

Most vaccines require several immunizations to induce robust immunity, and indeed, most SARS-CoV-2 vaccines require an initial two-shot regimen followed by several boosters to maintain efficacy. Such a complex series of immunizations unfortunately increases the cost and complexity of populations-scale vaccination and reduces overall compliance and vaccination rate. In a rapidly evolving pandemic affected by the spread of immune-escaping variants, there is an urgent need to develop vaccines capable of providing robust and durable immunity. In this work, a single immunization SARS-CoV-2 subunit vaccine is developed that can rapidly generate potent, broad, and durable humoral immunity. Injectable polymer-nanoparticle (PNP) hydrogels are leveraged as a depot technology for the sustained delivery of a nanoparticle antigen (RND-NP) displaying multiple copies of the SARS-CoV-2 receptor-binding domain (RBD) and potent adjuvants including CpG and 3M-052. Compared to a clinically relevant prime-boost regimen with soluble vaccines formulated with CpG/alum or 3M-052/alum adjuvants, PNP hydrogel vaccines more rapidly generated higher, broader, and more durable antibody responses. Additionally, these single-immunization hydrogel-based vaccines elicit potent and consistent neutralizing responses. Overall, it is shown that PNP hydrogels elicit improved anti-COVID immune responses with only a single administration, demonstrating their potential as critical technologies to enhance overall pandemic readiness.

Injectable Polymer‐Nanoparticle Hydrogel for the Sustained Intravitreal Delivery of Bimatoprost

AbstractVision impairment resulting from chronic eye diseases, such as macular degeneration and glaucoma, severely impacts patients’ quality of life and poses an immense global financial burden. Current standard of care for such diseases includes daily eye drops or frequent intravitreal (ITV) injections, which are burdensome treatment modalities resulting in low patient compliance. There remains a growing need for easily administered long‐acting delivery technologies for prolonging exposure of ocular therapeutics with each administration. Here, this work deploys a supramolecular polymer‐nanoparticle (PNP) hydrogel for ITV delivery of the glaucoma drug bimatoprost. PNP hydrogels are shear‐thinning and self‐healing, key properties for injectability, and enable slow release of molecular cargo in vitreous humor (VH) mimics. An in vivo study in New Zealand white rabbits demonstrated intravitreally injected PNP hydrogels form depots that degrade slowly over time, maintaining detectable levels of bimatoprost in the VH up to 8 weeks following injection. Ophthalmic examinations and histopathology identified a mild foreign body response (FBR) to the hydrogel, characterized by rare clusters of foamy macrophages and giant cells associated with minimal, patchy fibroplasia. This work shows that PNP hydrogels exhibit numerous desirable traits for sustained drug delivery and further work will be necessary to optimize tolerability in the eye.

Injectable Nanoparticle-Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies.

When properly deployed, the immune system can eliminate deadly pathogens, eradicate metastatic cancers, and provide long‐lasting protection from diverse diseases. Unfortunately, realizing these remarkable capabilities is inherently risky as disruption to immune homeostasis can elicit dangerous complications or autoimmune disorders. While current research is continuously expanding the arsenal of potent immunotherapeutics, there is a technological gap when it comes to controlling when, where, and how long these drugs act on the body. Here, this study explored the ability of a slow‐releasing injectable hydrogel depot to reduce dose‐limiting toxicities of immunostimulatory CD40 agonist (CD40a) while maintaining its potent anticancer efficacy. A previously described polymer‐nanoparticle (PNP) hydrogel system is leveraged that exhibits shear‐thinning and yield‐stress properties that are hypothesized to improve locoregional delivery of CD40a immunotherapy. Using positron emission tomography, it is demonstrated that prolonged hydrogel‐based delivery redistributes CD40a exposure to the tumor and the tumor draining lymph node (TdLN), thereby reducing weight loss, hepatotoxicity, and cytokine storm associated with standard treatment. Moreover, CD40a‐loaded hydrogels mediate improved local cytokine induction in the TdLN and improve treatment efficacy in the B16F10 melanoma model. PNP hydrogels, therefore, represent a facile, drug‐agnostic method to ameliorate immune‐related adverse effects and explore locoregional delivery of immunostimulatory drugs.

Extreme Extensibility in Physically Cross-Linked Nanocomposite Hydrogels Leveraging Dynamic Polymer-Nanoparticle Interactions.

Designing yield stress fluids to exhibit desired functional properties is an integral challenge in many applications such as 3D printing, drilling, food formulation, fiber spinning, adhesives, and injectable biomaterials. Extensibility in particular has been found to be a highly beneficial characteristic for materials in these applications; however, few highly extensible, high water content materials have been reported to date. Herein we engineer a class of high water content nanocomposite hydrogel materials leveraging multivalent, noncovalent, polymer–nanoparticle (PNP) interactions between modified cellulose polymers and biodegradable nanoparticles. We show that modulation of the chemical composition of the PNP hydrogels controls the dynamic cross-linking interactions within the polymer network and directly impacts yielding and viscoelastic responses. These materials can be engineered to stretch up to 2000% strain and occupy an unprecedented property regime for extensible yield stress fluids. Moreover, a dimensional analysis of the relationships between extensibility and the relaxation and recovery time scales of these nanocomposite hydrogels uncovers generalizable design criteria that will be critical for future development of extensible materials.

Thermal-Switchable, Trifunctional Ceramic-Hydrogel Nanocomposites Enable Full-Lifecycle Security in Practical Battery Systems.

Thermal runaway (TR) failures of large-format lithium-ion battery systems related to fires and explosions have become a growing concern. Here, we design a smart ceramic-hydrogel nanocomposite that provides integrated thermal management, cooling, and fire insulation functionalities and enables full-lifecycle security. The glass-ceramic nanobelt sponges exhibit high mechanical flexibility with 80% reversible compressibility and high fatigue resistance, which can firmly couple with the polymer-nanoparticle hydrogels and form thermal-switchable nanocomposites. In the operating mode, the high enthalpy of the nanocomposites enables efficient thermal management, thereby preventing local temperature spikes and overheating under extremely fast charging conditions. In the case of mechanical or thermal abuse, the stored water can be immediately released, leaving behind a highly flexible ceramic matrix with low thermal conductivity (42 mW m-1 K-1 at 200 °C) and high-temperature resistance (up to 1300 °C), thus effectively cooling the TR battery and alleviating the devastating TR propagation. The versatility, self-adaptivity, environmental friendliness, and manufacturing scalability make this material highly attractive for practical safety assurance applications.

PNP Hydrogel Prevents Formation of Symblephara in Mice After Ocular Alkali Injury.

PurposeTo create an alkali injury symblephara mouse model to study conjunctival fibrosis pathophysiology and test polymer nanoparticle (PNP) hydrogel as a preventative therapeutic.MethodsMice were injured using NaOH-soaked filter paper to determine the optimal NaOH concentration to induce the formation of symblephara. Injured mice were observed for 7 days to detect the formation of symblephara. Forniceal shortening observed on hematoxylin and eosin (H&E)-stained tissue sections was used as a symblephara marker. Alpha-smooth muscle actin (α-SMA) expression, Masson's trichrome assay, and periodic acid–Schiff (PAS) staining were used to determine myofibroblast expression, collagen deposition, and goblet cell integrity. PNP hydrogel, with multivalent, noncovalent interactions between modified biopolymers and nanoparticles, was applied immediately after alkali injury to determine its ability to prevent the formation of symblephara.ResultsForniceal shortening was observed in H&E images with 1N NaOH for 2 minutes after 7 days without globe destruction. PNP hydrogel prevented forniceal shortening after alkali injury as observed by H&E histology. α-SMA expression and collagen deposition in eye tissue sections were increased in the fornix after injury with 1N NaOH compared with uninjured controls. PNP hydrogel treatment immediately after injury reduced α-SMA expression and collagen deposition in the forniceal region. Mucin-secreting goblet cells stained with PAS were significantly lower in alkali-injured and PNP hydrogel–treated conjunctivas than in uninjured control conjunctivas.ConclusionsWe observed that 1N NaOH for 2 minutes induced maximal forniceal shortening and symblephara in mice. PNP hydrogel prevented forniceal shortening and conjunctival fibrosis after injury. This first murine model for symblephara will be useful to study fibrosis pathophysiology after conjunctival injury and to determine therapeutic targets for cicatrizing diseases.Translational RelevanceThis mouse model of symblephara can be useful for studying conjunctival scarring disease pathophysiology and preventative therapeutics. We tested PNP hydrogel, which prevented the formation of symblephara after injury.

Supramolecular Reinforcement of Polymer–Nanoparticle Hydrogels for Modular Materials Design

AbstractMoldable hydrogels are increasingly used as injectable or extrudable materials in biomedical and industrial applications owing to their ability to flow under applied stress (shear‐thin) and reform a stable network (self‐heal). Nanoscale components can be added to dynamic polymer networks to modify their mechanical properties and broaden the scope of applications. Viscoelastic polymer–nanoparticle (PNP) hydrogels comprise a versatile and tunable class of dynamic nanocomposite materials that form via reversible interactions between polymer chains and nanoparticles. However, PNP hydrogel formation is restricted to specific interactions between select polymers and nanoparticles, resulting in a limited range of mechanical properties and constraining their utility. Here, a facile strategy to reinforce PNP hydrogels through the simple addition of α‐cyclodextrin (αCD) to the formulation is introduced. The formation of polypseudorotoxanes between αCD and the hydrogel components resulted in a drastic enhancement of the mechanical properties. Furthermore, supramolecular reinforcement of CD–PNP hydrogels enabled decoupling of the mechanical properties and material functionality. This allows for modular exchange of structural components from a library of functional polymers and nanoparticles. αCD supramolecular binding motifs are leveraged to form CD–PNP hydrogels with biopolymers for high‐fidelity 3D (bio)printing and drug delivery as well as with inorganic NPs to engineer magnetic or conductive materials.

Lignin nanoparticles for hydrogel-based pressure sensor

The preparation of high lignin content hydrogels with good mechanical and multifunctional properties remains a huge challenge. In this study, a novel polymer-nanoparticle hydrogel was developed by a covalent crosslinking strategy, which not only preserved the characteristics of nanoparticles but also gives them good mechanical properties. Herein, lignin-silver nanoparticles (Lig-Ag NPs) were prepared from industrial lignin starting material and crosslinked into hydrogel with poly(ethylene glycol) diglycidyl ether. The obtained hydrogel (Lig-Ag NPs/PEG, LANP) exhibited good mechanical properties (elongation at break 53%, tensile strength 94.67 kPa, toughness 277.32 kJ m−3), adhesiveness, conductivity, pressure- and pH-stimuli-responsiveness, which benefited from the appropriate degree of crosslink, the generated catechol groups and redox-active quinone/semiquinone free radicals from Lig-Ag NPs. These functional properties can also be tuned by the contents of Lig-Ag NPs. Based on the above properties, a LANP sensor was assembled and showed good application for pressure- and pH-monitoring. This work provides a green and facile strategy of lignin valorization towards new multi-functional and smart applications.

Gelation and yielding behavior of polymer-nanoparticle hydrogels.

Polymer–nanoparticle hydrogels are a unique class of self‐assembled, shear‐thinning, yield‐stress fluids that have demonstrated potential utility in many impactful applications. Here, we present a thorough analysis of the gelation and yielding behavior of these materials with respect to the polymer and nanoparticle component stoichiometry. Through comprehensive rheological and diffusion studies, we reveal insights into the structural dynamics of the polymer nanoparticle network that identify that stoichiometry plays a key role in gelation and yielding, ultimately enabling the development of hydrogel formulations with unique shear‐thinning and yield‐stress behaviors. Access to these materials opens new doors for interesting applications in a variety of fields including tissue engineering, drug delivery, and controlled solution viscosity.

Hydrogel-Based Slow Release of a Receptor-Binding Domain Subunit Vaccine Elicits Neutralizing Antibody Responses Against SARS-CoV-2.

The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID‐19. The receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, clinically‐relevant adjuvants Alum, AddaVax, and CpG/Alum are found unable to elicit neutralizing responses following a prime‐boost immunization. Here, it has been shown that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer‐nanoparticle (PNP) hydrogel elicited potent anti‐RBD and anti‐spike antibody titers, providing broader protection against SARS‐CoV‐2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically‐relevant adjuvant systems. Notably, a SARS‐CoV‐2 spike‐pseudotyped lentivirus neutralization assay revealed that hydrogel‐based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.

Hierarchical biomaterials via photopatterning-enhanced direct ink writing

Recent advances in additive manufacturing (AM) technologies provide tools to fabricate biological structures with complex three-dimensional (3D) organization. Deposition-based approaches have been exploited to manufacture multimaterial constructs. Stimulus-triggered approaches have been used to fabricate scaffolds with high resolution. Both features are useful to produce biomaterials that mimic the hierarchical organization of human tissues. Recently, multitechnology biofabrication approaches have been introduced that integrate benefits from different AM techniques to enable more complex materials design. However, few methods allow for tunable properties at both micro- and macro-scale in materials that are conducive for cell growth. To improve the organization of biofabricated constructs, we integrated direct ink writing (DIW) with digital light processing (DLP) to form multimaterial constructs with improved spatial control over final scaffold mechanics. Polymer–nanoparticle hydrogels were combined with methacryloyl gelatin (GelMA) to engineer dual inks that were compatible with both DIW and DLP. The shear-thinning and self-healing properties of the dual inks enabled extrusion-based 3D printing. The inclusion of GelMA provided a handle for spatiotemporal control of cross-linking with DLP. Exploiting this technique, complex multimaterial constructs were printed with defined mechanical reinforcement. In addition, the multitechnology approach was used to print live cells for biofabrication applications. Overall, the combination of DIW and DLP is a simple and efficient strategy to fabricate hierarchical biomaterials with user-defined control over material properties at both micro- and macro-scale.

Injectable Supramolecular Polymer-Nanoparticle Hydrogels for Cell and Drug Delivery Applications

These methods describe how to formulate injectable, supramolecular polymer-nanoparticle (PNP) hydrogels for use as biomaterials. PNP hydrogels are composed of two components: hydrophobically modified cellulose as the network polymer and self-assembled core-shell nanoparticles that act as non-covalent cross linkers through dynamic, multivalent interactions. These methods describe both the formation of these self-assembled nanoparticles through nanoprecipitation as well as the formulation and mixing of the two components to form hydrogels with tunable mechanical properties. The use of dynamic light scattering (DLS) and rheology to characterize the quality of the synthesized materials is also detailed. Finally, the utility of these hydrogels for drug delivery, biopharmaceutical stabilization, and cell encapsulation and delivery is demonstrated through in vitro experiments to characterize drug release, thermal stability, and cell settling and viability. Due to its biocompatibility, injectability, and mild gel formation conditions, this hydrogel system is a readily tunable platform suitable for a range of biomedical applications.

Injectable Supramolecular Polymer-Nanoparticle Hydrogels for Cell and Drug Delivery Applications.

These methods describe how to formulate injectable, supramolecular polymer-nanoparticle (PNP) hydrogels for use as biomaterials. PNP hydrogels are composed of two components: hydrophobically modified cellulose as the network polymer and self-assembled core-shell nanoparticles that act as non-covalent cross linkers through dynamic, multivalent interactions. These methods describe both the formation of these self-assembled nanoparticles through nanoprecipitation as well as the formulation and mixing of the two components to form hydrogels with tunable mechanical properties. The use of dynamic light scattering (DLS) and rheology to characterize the quality of the synthesized materials is also detailed. Finally, the utility of these hydrogels for drug delivery, biopharmaceutical stabilization, and cell encapsulation and delivery is demonstrated through in vitro experiments to characterize drug release, thermal stability, and cell settling and viability. Due to its biocompatibility, injectability, and mild gel formation conditions, this hydrogel system is a readily tunable platform suitable for a range of biomedical applications.

Dynamic Hydrogels for Prevention of Post‐Operative Peritoneal Adhesions

AbstractPost‐operative adhesions are fibrous bands of scar tissue formed between internal tissues and organs causing clinical morbidity and their prevention represents a critical unmet need. Over 20 million Americans undergo invasive surgery each year and 95% of those patients develop post‐operative adhesions. More specifically, peritoneal adhesions forming as a result of abdominal surgery can result in severe complications such as chronic pain or adhesive small bowel obstruction requiring secondary adhesiolysis surgery. Additionally, adhesiolysis increases operation times during reoperative procedures and increases the risk of hemorrhage and organ injury upon reentry. This work reports the use of a dynamically crosslinked polymer‐nanoparticle (PNP) hydrogel adhesion barrier comprised of hydrophobically modified hydroxypropylmethylcellulose and biodegradable PEG‐PLA nanoparticles. These materials have desirable viscoelastic and flow properties, long‐term physical stability during storage, permit administration via spraying, enable local retention in the abdominal cavity for 2 weeks, and definitively reduce peritoneal adhesion formation. Using a rodent ischemic button model to generate peritoneal adhesions (n > 4), the PNP hydrogel significantly reduced peritoneal adhesion severity compared to commercial control products when assessed by a standardized 5‐point scale (3.18 ± 1.07 versus 1.35 ± 0.63; p = 0.0014). These results suggest that the PNP hydrogel adhesion barrier is a simple and effective solution for the prevention of peritoneal adhesions.

Prolonged Codelivery of Hemagglutinin and a TLR7/8 Agonist in a Supramolecular Polymer-Nanoparticle Hydrogel Enhances Potency and Breadth of Influenza Vaccination.

The sustained release of vaccine cargo has been shown to improve humoral immune responses to challenging pathogens such as influenza. Extended codelivery of antigen and adjuvant prolongs germinal center reactions, thus improving antibody affinity maturation and the ability to neutralize the target pathogen. Here, we develop an injectable, physically cross-linked polymer–nanoparticle (PNP) hydrogel system to prolong the local codelivery of hemagglutinin and a toll-like receptor 7/8 agonist (TLR7/8a) adjuvant. By tethering the TLR7/8a to a NP motif within the hydrogels (TLR7/8a-NP), the dynamic mesh of the PNP hydrogels enables codiffusion of the adjuvant and protein antigen (hemagglutinin), therefore enabling sustained codelivery of these two physicochemically distinct molecules. We show that subcutaneous delivery of PNP hydrogels carrying hemagglutinin and TLR7/8a-NP in mice improves the magnitude and duration of antibody titers in response to a single injection vaccination compared to clinically used adjuvants. Furthermore, the PNP gel-based slow delivery of influenza vaccines led to increased breadth of antibody responses against future influenza variants, including a future pandemic variant, compared to clinical adjuvants. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of influenza subunit vaccines.

Controlled delivery of gold nanoparticle-coupled miRNA therapeutics via an injectable self-healing hydrogel.

Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in vitro in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel in vitro demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears via the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs in vitro and has potential for in vivo applications.

Injectable Polymer-Nanoparticle Hydrogels for Local Immune Cell Recruitment.

The ability to engineer immune function has transformed modern medicine, highlighted by the success of vaccinations and recent efforts in cancer immunotherapy. Further directions in programming the immune system focus on the design of immunomodulatory biomaterials that can recruit, engage with, and program immune cells locally in vivo. Here, we synthesized shear-thinning and self-healing polymer-nanoparticle (PNP) hydrogels as a tunable and injectable biomaterial platform for local dendritic cell (DC) recruitment. PNP gels were formed from two populations of poly(ethylene glycol)-block-polylactide (PEG-b-PLA) NPs with the same diameter but different PEG brush length (2 or 5 kDa). PEG-b-PLA NPs with the longer PEG brush exhibited improved gel formation following self-assembly and faster recovery after shear-thinning. In all cases, model protein therapeutics were released via Fickian diffusion in vitro, and minor differences in the release rate between the gel formulations were observed. PNP hydrogels were loaded with the DC cytokine CCL21 and injected subcutaneously in a murine model. CCL21-loaded PNP hydrogels recruited DCs preferentially to the site of injection in vivo relative to non-CCL21-loaded hydrogels. Thus, PNP hydrogels comprise a simple and tunable platform biomaterial for in vivo immunomodulation following minimally invasive subcutaneous injection.

Injectable supramolecular polymer-nanoparticle hydrogels enhance human mesenchymal stem cell delivery.

Stem cell therapies have emerged as promising treatments for injuries and diseases in regenerative medicine. Yet, delivering stem cells therapeutically can be complicated by invasive administration techniques, heterogeneity in the injection media, and/or poor cell retention at the injection site. Despite these issues, traditional administration protocols using bolus injections in a saline solution or surgical implants of cell‐laden hydrogels have highlighted the promise of cell administration as a treatment strategy. To address these limitations, we have designed an injectable polymer–nanoparticle (PNP) hydrogel platform exploiting multivalent, noncovalent interactions between modified biopolymers and biodegradable nanoparticles for encapsulation and delivery of human mesenchymal stem cells (hMSCs). hMSC‐based therapies have shown promise due to their broad differentiation capacities and production of therapeutic paracrine signaling molecules. In this work, the fundamental hydrogel mechanical properties that enhance hMSC delivery processes are elucidated using basic in vitro models. Further, in vivo studies in immunocompetent mice reveal that PNP hydrogels enhance hMSC retention at the injection site and retain administered hMSCs locally for upwards of 2 weeks. Through both in vitro and in vivo experiments, we demonstrate a novel scalable, synthetic, and biodegradable hydrogel system that overcomes current limitations and enables effective cell delivery.