Injectable hydrogels are useful for numerous biomedical applications, such as to introduce therapeutics into tissues or for 3D printing. To expand the complexity of available injectable hydrogels, ...shear‐thinning and self‐healing granular hydrogels are developed from microgels that interact via guest–host chemistry. The microgel properties (e.g., degradation, molecule release) are tailored through their crosslinking chemistry, including degradation in response to proteases. When microgels of varied formulations are mixed, complex release and degradation behaviors are observed, including after injection to permit cellular invasion.
A modular, guest–host‐mediated approach is used to design an injectable granular hydrogel. Tunable microgels are formed into granular structures that exhibit multiplexed properties based on their microgel design. This generalizable strategy allows complex material design through individual microgels that respond to their local environment.
Supramolecular chemistry has emerged as an important technique for the formation of biomaterials, including nano- and microparticles and hydrogels. One specific class of supramolecular chemistry is ...the direct association of guest–host pairs, which involves host macrocycles such as cyclodextrins and cucurbitnurils and a wide range of guest molecules, where association is typically driven by molecule size and hydrophobicity. These systems are of particular interest in the biomedical field due to their dynamic nature, chemical diversity, relative ease of synthesis, and ability to interact with biological or synthetic molecules. In this review, we discuss aspects of polymeric material assembly mediated by guest–host interactions, including the fundamentals of assembly into functional biomedical materials. Additionally, applications of biomaterials that utilize guest–host interactions are discussed with a focus on injectable material formulations, the sequestration and delivery of encapsulated cargo (i.e., drugs, biomolecules), and the investigation of cell–material interactions (i.e., adhesion, differentiation, and delivery). While methodologies for guest–host mediated assembly and biological interaction have rapidly evolved in recent years, they remain far from realizing their full potential in the biomaterials field.
Shear‐thinning hydrogels are useful for biomedical applications, from 3D bioprinting to injectable biomaterials. Although they have the appropriate properties for injection, it may be advantageous to ...decouple injectability from the controlled release of encapsulated therapeutics. Toward this, composites of hydrogels and encapsulated microgels are introduced with microgels that are fabricated via microfluidics. The microgel cross‐linker controls degradation and entrapped molecule release, and the concentration of microgels alters composite hydrogel rheological properties. For the treatment of myocardial infarction (MI), interleukin‐10 (IL‐10) is encapsulated in microgels and released from composites. In a rat model of MI, composites with IL‐10 reduce macrophage density after 1 week and improve scar thickness, ejection fraction, cardiac output, and the size of vascular structures after 4 weeks when compared to saline injection. Improvements are also observed with the composite without IL‐10 over saline, emphasizing the role of injectable hydrogels alone on tissue repair.
Guest–host hyaluronic acid hydrogels are combined with covalently cross‐linked hyaluronic acid microgels with encapsulated therapeutics to create composites that are injectable and can deliver therapeutics with controlled release kinetics. Here, feasibility is demonstrated using composite hydrogels to deliver interleukin‐10 in a rat MI model.
Self-assembled and injectable hydrogels have many beneficial properties for the local delivery of therapeutics; however, challenges still exist in the sustained release of small molecules from these ...highly hydrated networks. Host-guest chemistry between cyclodextrin and adamantane has been used to create supramolecular hydrogels from modified polymers. Beyond assembly, this chemistry may also provide increased drug retention and sustained release through the formation of inclusion complexes between drugs and cyclodextrin. Here, we engineered a two-component system from adamantane-modified and β-cyclodextrin (CD)-modified hyaluronic acid (HA), a natural component of the extracellular matrix, to produce hydrogels that are both injectable and able to sustain the release of small molecules. The conjugation of cyclodextrin to HA dramatically altered its affinity for hydrophobic small molecules, such as tryptophan. This interaction led to lower molecule diffusivity and the release of small molecules for up to 21 days with release profiles dependent on CD concentration and drug-CD affinity. There was significant attenuation of release from the supramolecular hydrogels (~20% release in 24h) when compared to hydrogels without CD (~90% release in 24h). The loading of small molecules also had no effect on hydrogel mechanics or self-assembly properties. Finally, to illustrate this controlled delivery approach with clinically used small molecule pharmaceuticals, we sustained the release of two widely used drugs (i.e., doxycycline and doxorubicin) from these hydrogels.
The development of multifunctional nanoparticles for medical applications is of growing technological interest. A single formulation containing imaging and/or drug moieties that is also capable of ...preferential uptake in specific cells would greatly enhance diagnostics and treatments. There is growing interest in plant-derived viral nanoparticles (VNPs) and establishing new platform technologies based on these nanoparticles inspired by nature. Cowpea mosaic virus (CPMV) serves as the standard model for VNPs. Although exterior surface modification is well-known and has been comprehensively studied, little is known of interior modification. Additional functionality conferred by the capability for interior engineering would be of great benefit toward the ultimate goal of targeted drug delivery. Here, we examined the capacity of empty CPMV (eCPMV) particles devoid of RNA to encapsulate a wide variety of molecules. We systematically investigated the conjugation of fluorophores, biotin affinity tags, large molecular weight polymers such as poly(ethylene glycol) (PEG), and various peptides through targeting reactive cysteines displayed selectively on the interior surface. Several methods are described that mutually confirm specific functionalization of the interior. Finally, CPMV and eCPMV were labeled with near-infrared fluorophores and studied side-by-side in vitro and in vivo. Passive tumor targeting via the enhanced permeability and retention effect and optical imaging were confirmed using a preclinical mouse model of colon cancer. The results of our studies lay the foundation for the development of the eCPMV platform in a range of biomedical applications.
Strategic delivery of biomaterials to the newly formed myocardial infarction (MI) continues to be an area of active investigation and offers the opportunity to reappraise the use of small molecule ...therapeutics that hold high target specificity but are problematic when systemically delivered. The goal of this study was to examine the effects of late post-MI delivery (3 days post-MI) of a self-assembling hydrogel (SAgel), which had been loaded with a previously characterized matrix metalloproteinase inhibitor (MMPi).
Using a minimally invasive (mini-thoracotomy) and an SAgel allowing for targeted myocardial injection array within the MI region of a large animal model as well as localized release of an MMPi, improved LV function and geometry would be demonstrated up to 28 days post-MI.
MI was induced in adult pigs (25 kg) by left anterior descending (LAD) catheter balloon occlusion (90 min/then reperfusion) and at 3 days post-MI randomized to MI-SAgel/SD7300 (500 μg/mL; n=7) or saline (MI saline; n=8), whereby the injections were performed in a 9 point 100 uL array within the targeted LAD region. The SAgel adapts fluid-like properties to flow through the syringe (21 Gauge) due to shear forces during injection and rapidly reassembles with encapsulated SD7300 following injection into the MI region. LV ejection fraction (LVEF) and end-diastolic volume (LVEDV) were measured at Baseline (pre-MI) and at 14 and 28 days post-MI by echocardiography. LVEF fell post-MI but was significantly attenuated by SAgel/SD7300 injections. LVEDV increased from Baseline (35±2 mL) in the MI-saline (84+6) and MI-SAgel/SD7300 (64+4 mL groups at 28 days post-MI (p<0.05)) but was lower in the MI-SAgel/SD7300 group (p<0.05).
This is the first study to demonstrate the feasibility of targeted delivery of a self-assembling injectable gel using a minimally invasive surgical approach at a relevant post-MI time point. Second, targeted delivery of this gel containing an MMPi for sustained local release demonstrated sustained beneficial effects on post-MI remodeling.
Adverse left ventricular (LV) remodeling following myocardial infarction (MI) involves associated changes in extracellular proteolytic activity and LV biomechanics. This study evaluates how targeted ...injections of a self-assembling hydrogel (SAgel) loaded with SD-7300, an established matrix metalloproteinase inhibitor (MMPi), impacts regional LV biomechanics post-MI.
We hypothesize that delivery of SD-7300 to the MI region will attenuate post-MI changes in biomechanics throughout the LV.
Mature pigs (25 kg; n=15) were subjected to an ischemia-reperfusion model in which MI is induced by left anterior descending occlusion. At three days post-MI, a subset of pigs were injected with 500μg/mL of SAgel/SD7300 (MI/MMPi; n=7) in a 9 point 100µL array spanning the MI region while the remaining pigs served as controls (MI only; n=8). Peak strain (εpeak) and systolic strain rate (γsys), indices of systolic function, were assessed by speckle-tracking echocardiography at baseline and at 28 days post-MI. Regional diastolic myocardial stiffness (Km), an index of diastolic function, was computed from stress-strain relations developed at both time points.
While global εpeak (Fig 1A) and global γsys (Fig 1B) were reduced at 28 days post-MI in both groups (p < 0.05), values were significantly higher in the MI/MMPi group (p < 0.05). Regional Km (Fig 1C) was significantly lower in the MI/MMPi group relative to MI only in the border zone (3.5 ± 0.4kPa vs. 8.9 ± 1.2kPa, p < 0.05) and remote myocardium (5.4 ± 0.6kPa vs. 7.9 ± 0.7kPa, p < 0.05).
Localized delivery of MMPi mechanically stabilizes the MI region and also impacts border zone and remote myocardial biomechanics over 28 days post-MI. Injectable biomaterials enable the repurposing of an established MMPi for attenuation of post-MI remodeling.
Guest-host chemistry is an emerging tool in the preparation of biomaterials. Towards the design of hydrogels, guest-host chemistry has been used to impart unique shear-thinning and self-healing ...properties that allow these materials to be injected through syringes and catheters as a single component, avoiding complications associated with traditional covalent systems. As a treatment for myocardial infarction, injectable guest-host hydrogels may be injected directly into the myocardial wall and have shown therapeutic benefit in a number of strategies, including drug delivery, cell delivery, and tissue bulking. As delivery systems, injectable hydrogels provide controlled release of payloads that attenuate maladaptive remodeling of the left ventricle, by inhibiting expression of proteases, recruiting cells to the region, or otherwise stimulating therapeutic biological processes such as angiogenesis. Guest-host biomaterials must be refined and advanced to overcome challenges associated with delivering therapeutics in these areas, as well as to provide novel materials platforms for investigating therapeutic delivery in the future. This dissertation describes the engineering of two injectable hydrogel platforms that address challenges in the delivery of therapeutics after myocardial infarction. Each of these systems is investigated both in vitro for an understanding of material properties and the parameters that tune them, as well as in vivo, in a number of clinically relevant animal models and therapeutic targets. In the first aim of this thesis, isotropic guest-host hydrogels are designed for the sustained release of a variety of small molecules. Through the control of small molecule binding with cyclodextrin host moieties engineered in the hydrogel, we show that both cyclodextrin content and molecule affinity for cyclodextrin are critical factors that provide tunable release of small molecules from these systems. Furthermore, we demonstrate that this system is broadly applicable to the release of a number of pharmaceutical small molecule payloads. In the second aim of this thesis, isotropic guest-host hydrogels are specifically formulated for the delivery of the small molecule protease inhibitor SD-7300, a therapeutic requiring local delivery after myocardial infarction. Here we demonstrate that the engineered guest-host hydrogels provide sustained release and retain activity of this molecule, which in turn provides improved functional and biological outcomes in a large-animal model of myocardial infarction. In the third aim of this thesis, guest-host chemistry is utilized to assemble microstructured granular hydrogels for the design of multifunctional material platforms. Granular hydrogels are demonstrated to have disease responsivity in myocardial infarction, and functional benefit through the delivery of the chemokine SDF-1α.
Self-assembled and injectable hydrogels have many beneficial properties for the local delivery of therapeutics; however, challenges still exist in the sustained release of small molecules from these ...highly hydrated networks. Host-guest chemistry between β-cyclodextrin (CD) and adamantane has been used to create supramolecular hydrogels from modified polymers. Beyond assembly, this chemistry may also provide increased drug retention and sustained release through the formation of inclusion complexes between drugs and CD. Here, we engineered a two-component system from adamantane-modified and CD-modified hyaluronic acid (HA), a natural component of the extracellular matrix, to produce hydrogels that are both injectable and able to sustain the release of small molecules. The conjugation of CD to HA dramatically altered its affinity for hydrophobic small molecules, such as tryptophan. This interaction led to lower molecule diffusivity and the release of small molecules for up to 21 days with release profiles dependent on CD concentration and drug-CD affinity. There was significant attenuation of release from the supramolecular hydrogels (∼20% release in 24 h) when compared to hydrogels without CD (∼90% release in 24 h). The loading of small molecules also had no effect on hydrogel mechanics or self-assembly properties. Finally, to illustrate this controlled delivery approach with clinically used small molecule pharmaceuticals, we sustained the release of two widely used drugs (
i.e.
, doxycycline and doxorubicin) from these hydrogels.
Shear-thinning hyaluronic acid hydrogels based on modifications of β-cyclodextrin and adamantane were developed for the tunable, sustained release of small molecules, through regulation of cyclodextrin content and affinity for cyclodextrin.
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