Showing papers by "Jason A. Burdick published in 2010"

Injectable hydrogel properties influence infarct expansion and extent of postinfarction left ventricular remodeling in an ovine model

Abstract: A recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (approximately 8 versus approximately 43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.

Spatially controlled hydrogel mechanics to modulate stem cell interactions

Abstract: Local control of the stem cell microenvironment with biomaterial design is of critical importance for tissue engineering. Matrix mechanics is one aspect of biomaterial design that has received considerable attention recently due to the effect of mechanics on stem cell proliferation, morphology, and differentiation. In order to investigate the effect of locally controlled mechanics on human mesenchymal stem cells (hMSCs), a sequentially crosslinked hyaluronic acid hydrogel system was developed that permits spatial patterning of mechanics (distinct patterns and gradients). Methacrylated hyaluronic acid was synthesized to allow for crosslinking via both Michael-type addition using a dithiol and radical polymerization using light. By varying the initial methacrylate consumption through addition crosslinking, restricting UV light to specified regions, and varying UV exposure time, a wide range of mechanics (from ∼3 kPa to ∼100 kPa) was possible in both uniform and patterned hydrogels. hMSCs exhibited increased spreading and proliferation on stiffer gels compared to cells cultured on softer gels. Furthermore, cells grown on gels with patterned mechanics exhibited spreading and proliferation behavior that correlated with the local mechanics. This method to spatially control matrix mechanics represents a novel hydrogel system to tune the stem cell microenvironment.

Controlling stem cell fate with material design.

Abstract: Advances in our understanding of stem cell interactions with their environment are leading to the development of new materials-based approaches to control stem cell behavior toward cellular culture and tissue regeneration applications. Materials can provide cues based on chemistry, mechanics, structure, and molecule delivery that control stem cell fate decisions and matrix formation. These approaches are helping to advance clinical translation of a range of stem cell types through better expansion techniques and scaffolding for use in tissue engineering approaches for the regeneration of many tissues. With this in mind, this progress report covers basic concepts and recent advances in the use of materials for manipulating stem cells.

Light-responsive biomaterials: development and applications.

Abstract: Novel biomaterials are beneficial to the growing fields of drug delivery, cell biology, micro-devices, and tissue engineering. With recent advances in chemistry and materials science, light is becoming an attractive option as a method to control biomaterial behavior and properties. In this Feature Article, we explore some of the early and recent advances in the design of light-responsive biomaterials. Particular attention is paid to macromolecular assemblies for drug delivery, multi-component surface patterning for advanced cell assays, and polymer networks that undergo chemical or shape changes upon light exposure. We conclude with some remarks about future directions of the field.

Solvent induced transition from wrinkles to creases in thin film gels with depth-wise crosslinking gradients

Abstract: We investigated solvent induced transition of surface instability from wrinkles to creases in poly(2-hydroxyethyl methacrylate) (PHEMA) gels with depth-wise crosslinking gradients. The mode of surface instability and morphology of surface patterns was found to be dependent on the equilibrium linear expansion, which was a function of crosslinker concentration and the solvent–polymer interaction. The maximum linear expansion was obtained when the PHEMA film was swollen in a good solvent, which had the Hildebrand solubility parameter (δs) close to that of PHEMA gels, 26.6 to 29.6 MPa1/2. In a relatively poor solvent (e.g. water), wrinkling patterns were obtained and the morphoplogy was determined by the concentration of the crosslinker, ethylene glycol dimethacrylate (EGDMA). In a good solvent, such as alcohol and alcohol/water mixture, the equilibrium linear expansion ratio increased significantly, leading to the transition from wrinkling to creasing instability. In an ethanol/water mixture, we systematically varied the ratio between ethanol and water and observed the transition from wrinkling to creasing when gradually adding ethanol to water, and the reverse transition when adding water in ethanol. The onset of the linear expansion ratio for creasing (αc,c) was again found dependent on EGDMA concentration: αc,c ≈ 2.00 and 1.3, respectively, for gels with 1 and 3 wt% EGDMA. Finally, we demonstrated confinement of the creases by combining swelling and photopatterning.

Modular synthesis of biodegradable diblock copolymers for designing functional polymersomes.

Abstract: Polymer vesicles, or polymersomes, are promising candidates for applications in drug delivery and tissue imaging. While a vast variety of polymers have been explored for their ability to assemble into polymersomes, relatively little research on the functionalization of these polymers has been reported. We present here a novel route for the synthesis of poly(caprolactone)-b-poly(ethylene glycol) (PCL-b-PEG) diblock copolymers that allows for the insertion of functional groups at the block junctions and the assembly of functional membranes. This modular synthesis has been developed on the basis of solid-phase peptide synthesis techniques and is accomplished through the formation of two peptide bonds, one between an amine-terminated PEG and the carboxyl moiety of the functional group and the other between the functional group amine and a carboxy-terminated PCL. As a demonstration of the potential utility of the resulting vesicles, we incorporated two different amino acid functional groups at the junction. 2-...

Kinetic study of swelling-induced surface pattern formation and ordering in hydrogel films with depth-wise crosslinking gradient

Abstract: Hydrogels undergo extensive three-dimensional volume changes when immersed in water, the degree of which is determined by the network chemical composition and degree of crosslinking. When the hydrogel is attached to a rigid substrate, it swells preferentially perpendicular to the substrate. This anisotropic swelling generates a compressive stress, which drives the formation of surface patterns when exceeding a critical stress value (σ ≥ σc). In order to develop an indepth understanding of the mechanism of surface pattern formation in hydrogels, we investigated the dynamic evolution of surface patterns in photocured hydrogel films from poly(2-hydroxyethyl methacrylate) (PHEMA) crosslinked with different concentrations of ethylene glycol dimethacrylate (EGDMA, 0–3 wt%). During curing in the presence of oxygen, a modulus gradient along the film depth was generated due to oxygen inhibition of the radical polymerization near the film surface. The swelling-induced wrinkling pattern formation followed Fickian-type kinetics (λ ∼ t1/2) at early stages, which was independent of the final pattern morphology. The onset of wrinkling was found at a linear expansion of αc ≈ 1.12, which remained constant with increasing EGDMA concentration but decreased with increasing film thickness, indicating an increase in critical stress with crosslinker concentration. In contrast, the equilibrium linear expansion value, αe, decreased significantly (from 2.55 to 1.20) with increasing crosslinker concentration (from 0 to 3 wt%), resulting in transition from random patterns to highly ordered hexagonal structures.

Electrospun Fibrous Scaffolds with Multiscale and Photopatterned Porosity

Abstract: The structural and mechanical properties of tissue engineered environments are crucial for successful cellular growth and tissue repair. Electrospinning is gaining wide attention for the fabrication of tissue engineered scaffolds, but the small pore sizes of these scaffolds limit cell infiltration and construct vascularization. To address this problem, we have combined electrospinning with photopatterning to create multiscale porous scaffolds. This process retains the fibrous nature of the scaffolds and permits enhanced cellular infiltration and vascularization when compared to unpatterned scaffolds. This is the first time that photopatterning has been utilized with electrospun scaffolds and is only now possible with the electrospinning of reactive macromers.

Light-sensitive polypeptide hydrogel and nanorod composites.

Abstract: Stimuli-responsive hydrogels exhibit structural changes based on changes in local temperature or pH and analytes and are highly valued in fields ranging from controlled drug release to tissue repair and also in microdevices. Hydrogels that respond to external stimuli, such as light or magnetic fields, offer additional advantageswith respect to on-demandand triggered response. With this in mind, we formulated a composite of thermoreversible polypeptide-based hydrogels, formed from a genetically engineered multiblock polypeptide that exhibits a temperature-dependent transition from a solid to liquid state, and gold nanorods. Near-infrared-light (NIR) exposure of the nanorods induces local heating and, consequently, melting of the gels. These networks were explored for the controlled release of a macromolecule and the release profiles were controlled by the extent and timing of light exposure, including stepwise release with intermittent light. The infrared-lightcontrolled dissociation of these hydrogels offers unique opportunities, such as for the delivery of drugs and growth factors with transdermal light exposure or for incorporation of hydrogel actuators in microdevices. Smart biopolymeric hydrogels are a new generation of biomaterials that may exhibit reversible physicochemical changes in response to their environment. These stimuliresponsivegels arefindingapplications inmanyfields, suchas for the delivery of therapeutic molecules, biomedical devices, such as actuators and biosensors/diagnostics, and as scaffolds for tissue engineering and regenerative medicine. A unique feature of such materials is that they undergo significant conformational changes upon variation in one or more physicochemical stimuli such as pH, temperature, analytes, or light. Although many variables have been explored, hydrogels that reversibly respond to temperature changes have been the subject of major investigation over the past two decades. These thermoresponsive systems are typically centered around synthetic polymers suchas poly(N-isopropylacrylamide) (PNIPAm) and its derivatives or biomimetic elastin-based

The influence of fibrous elastomer structure and porosity on matrix organization.

Abstract: Fibrous scaffolds are finding wide use in the field of tissue engineering, as they can be designed to mimic many native tissue properties and structures (e.g., cardiac tissue, meniscus). The influence of fiber alignment and scaffold architecture on cellular interactions and matrix organization was the focus of this study. Three scaffolds were fabricated from the photocrosslinkable elastomer poly(glycerol sebacate) (PGS), with changes in fiber alignment (non-aligned (NA) versus aligned (AL)) and the introduction of a PEO sacrificial polymer population to the AL scaffold (composite (CO)). PEO removal led to an increase in scaffold porosity and maintenance of scaffold anisotropy, as evident through visualization, mechanical testing, and mass loss studies. Hydrated scaffolds possessed moduli that ranged between ∼3–240 kPa, failing within the range of properties (<300 kPa) appropriate for soft tissue engineering. CO scaffolds were completely degraded as early as 16 days, whereas NA and AL scaffolds had ∼90% mass loss after 21 days when monitored in vitro. Neonatal cardiomyocytes, used as a representative cell type, that were seeded onto the scaffolds maintained their viability and aligned along the surface of the AL and CO fibers. When implanted subcutaneously in rats, a model that is commonly used to investigate in vivo tissue responses to biomaterials, CO scaffolds were completely integrated at 2 weeks, whereas ∼13% and ∼16% of the NA and AL scaffolds, respectively remained acellular. However, all scaffolds were completely populated with cells at 4 weeks post-implantation. Polarized light microscopy was used to evaluate the collagen elaboration and orientation within the scaffold. An increase in the amount of collagen was observed for CO scaffolds and enhanced alignment of the nascent collagen was observed for AL and CO scaffolds compared to NA scaffolds. Thus, these results indicate that the scaffold architecture and porosity are important considerations in controlling tissue formation.

Photocleavable side groups to spatially alter hydrogel properties and cellular interactions

Abstract: Hydrogel systems with inducible variations in mechanical and chemical properties are of interest to many aspects of tissue engineering. Substrate-tethered hydrogel films, fabricated by copolymerization of hydroxyethylacrylate with the photolabile monomer 2-nitrobenzyl acrylate (2-NBA) and a crosslinker were shown to be responsive to UV light through cleavage of the 2-NBA moiety. The surface and bulk properties of the films were characterized by infrared spectroscopy and atomic force and confocal microscopy. At long irradiation times, a tripling of the swelling ratio and an order of magnitude decrease in gel modulus were observed, coupled with an increase in surface wettability. Following short exposures, the gels became resistant to protein and cell adhesion, a trend that was reversed with longer exposure times. Finally, high-fidelity patterns of gel swelling were fabricated through spatially selective irradiation by employing basic photomasks. These materials are useful for future studies for which spatial and temporal control of material properties and cellular interactions are desirable.

Identification of osteoconductive and biodegradable polymers from a combinatorial polymer library.

Abstract: Combinatorial polymer syntheses are now being utilized to create libraries of materials with potential utility for a wide variety of biomedical applications. We recently developed a library of photopolymerizable and biodegradable poly(beta-amino ester)s (PBAEs) that possess a range of tunable properties. In this study, the PBAE library was assessed for candidate materials that met design criteria (e.g., physical properties such as degradation and mechanical strength and in vitro cell viability and osteoconductive behavior) for scaffolding in mineralized tissue repair. The most promising candidate, A6, was then processed into three-dimensional porous scaffolds and implanted subcutaneously and only presented a mild inflammatory response. The scaffolds were then implanted intramuscularly and into a critical-sized cranial defect either alone or loaded with bone morphogenetic protein-2 (BMP-2). The samples in both locations displayed mineralized tissue formation in the presence of BMP-2, as evident through radiographs, micro-computed tomography, and histology, whereas samples without BMP-2 showed minimal or no mineralized tissue. These results illustrate a process to identify a candidate scaffolding material from a combinatorial polymer library, and specifically for the identification of an osteoconductive scaffold with osteoinductive properties via the inclusion of a growth factor.

Microsphere/nanofiber composites for delivery of drugs, growth factors, and other agents

Abstract: Provided are compositions that include polymeric fibers and microspheres entrapped within the fibers, the compositions being capable of controlled delivery of one or more agents while also maintaining their structural properties. Also provided are related methods of fabricating these compositions and methods of utilizing the compositions to deliver agents to a subject.

Screening materials and soluble compounds for mineralized tissue engineering

Abstract: As more materials and soluble molecules are developed, the ability to screen these materials for applications in tissue engineering becomes increasingly important. A combinatorial library of poly(s-amino ester)s was screened to identify an osteoconductive material based on material properties and cellular interactions. The optimal material, A6, was then implanted into a critical-sized cranial defect loaded with a known osteoinductive factor to promote mineralized tissue formation. The identification of new osteoinductive cues from a library of known compounds was completed using high-throughput screening techniques. Several potential ‘hits’ were then screened in a dose response study that found 5 compounds to be the most potent. These methods of rapidly identifying materials and compounds from large libraries will be increasingly important in the field of tissue engineering.