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Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking.

ABSTRACT: Injectable biomaterials alone may alter local tissue responses, including inflammatory cascades and matrix production (e.g. stimulatory dermal fillers are used as volumizing agents that induce collagen production). To expand upon the available material compositions and timing of presentation, a tunable hyaluronic acid (HA) and poly(lactide-co-glycolide) (PLGA) microsphere composite system was formulated and assessed in subcutaneous and cardiac tissues. HA functionalized with hydroxyethyl methacrylate (HeMA) was used as a precursor to injectable and degradable hydrogels that carry PLGA microspheres (~50 ?m diameter) to tissues, where the HA hydrogel degradation (~20 or 70 days) and quantity of PLGA microspheres (0-300 mgml(-1)) are readily varied. When implanted subcutaneously, faster hydrogel degradation and more microspheres (e.g. 75 mgml(-1)) generally induced more rapid tissue and cellular interactions and a greater macrophage response. In cardiac applications, tissue bulking may be useful to alter stress profiles and to stabilize the tissue after infarction, limiting left ventricular (LV) remodeling. When fast degrading HeMA-HA hydrogels containing 75 mgml(-1) microspheres were injected into infarcted tissue in sheep, LV dilation was limited and the thickness of the myocardial wall and the presence of vessels in the apical infarct region were increased ~35 and ~60%, respectively, compared to empty hydrogels. Both groups decreased volume changes and infarct areas at 8 weeks, compared to untreated controls. This work illustrates the importance of material design in expanding the application of tissue bulking composites to a range of biomedical applications.

SUBMITTER: Tous E

PROVIDER: S-EPMC3408556 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking.

Tous Elena E Weber Heather M HM Lee Myung Han MH Koomalsingh Kevin J KJ Shuto Takashi T Kondo Norihiro N Gorman Joseph H JH Lee Daeyeon D Gorman Robert C RC Burdick Jason A JA

Acta biomaterialia 20120529 9

Injectable biomaterials alone may alter local tissue responses, including inflammatory cascades and matrix production (e.g. stimulatory dermal fillers are used as volumizing agents that induce collagen production). To expand upon the available material compositions and timing of presentation, a tunable hyaluronic acid (HA) and poly(lactide-co-glycolide) (PLGA) microsphere composite system was formulated and assessed in subcutaneous and cardiac tissues. HA functionalized with hydroxyethyl methacr ...[more]

PMID: 22659176

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Project description:Expansion of myocardium after myocardial infarction (MI) has long been identified as the primary mechanism that drives adverse left ventricular (LV) remodeling towards heart failure and death. Direct injection of hydrogels into the myocardium to mechanically constrain the infarct has demonstrated promise in limiting its remodeling and expansion. Despite early successes, there remain open questions in the determination of optimal hydrogel therapies, key application characteristics for which include injected polymer volume, stiffness, and spatial placement. Addressing these questions is complicated by the substantial variations in infarct type and extent, as well as limited understanding of the underlying mechanisms. Herein, we present an investigation on how hydrogel inclusions affect the effective tissue-level stiffness and strain fields in myocardium using full three-dimensional (3D) finite element simulations at early and late post-MI time points. We calibrated our simulations to triaxial mechanical and structural measurements of cuboidal LV myocardial specimens of post-infarcted myocardium, 0 and 4 weeks post-MI, injected with a dual-crosslinking hyaluronic acid-based hydrogel. Simulations included multiple deformation modes that spanned the anticipated physiological range in order to assess the effects of variations in inclusion size, location, and modulus on tissue-level myocardial mechanics. We observed significant local stiffening in the hydrogel-injected specimens that was highly dependent on the volume and mechanical properties of the injected hydrogel. Simulations revealed that the primary effect of the injections under physiological loading was a reduction in myocardial strain. This result suggests that hydrogel injections reduce infarct expansion by limiting the peak strains over the cardiac cycle. Overall, our study indicated that modulation of local effective tissue stiffness and corresponding strain reduction are governed by the volume and stiffness of the hydrogel, but relatively insensitive to its transmural placement. These findings provide important insights into mechanisms for ameliorating post-MI remodeling, as well as guidance for the future design of post-MI therapies.

Project description:A reliable suspension-based platform for scaling engineered cardiac tissue (ECT) production from human induced pluripotent stem cells (hiPSCs) is crucial for regenerative therapies. Here, we compared the production and functionality of ECTs formed using our scaffold-based, engineered tissue microsphere differentiation approach with those formed using the prevalent scaffold-free aggregate platform. We utilized a microfluidic system for the rapid (1 million cells/min), high density (30, 40, 60 million cells/ml) encapsulation of hiPSCs within PEG-fibrinogen hydrogel microspheres. HiPSC laden-microspheres and aggregates underwent suspension-based cardiac differentiation in chemically defined media. In comparison to aggregates, microspheres maintained consistent size and shape initially, over time, and within and between batches. Initial size and shape coefficients of variation for microspheres were eight and three times lower, respectively, compared to aggregates. On day 10, microsphere cardiomyocyte (CM) content was 27% higher and the number of CMs per initial hiPSC was 250% higher than for aggregates. Contraction and relaxation velocities of microspheres were four and nine times higher than those of aggregates, respectively. Microsphere contractile functionality also improved with culture time, whereas aggregate functionality remained unchanged. Additionally, microspheres displayed improved β-adrenergic signaling responsiveness and uniform calcium transient propagation. Transcriptomic analysis revealed that while both microspheres and aggregates demonstrated similar gene regulation patterns associated with cardiomyocyte differentiation, heart development, cardiac muscle contraction, and sarcomere organization, the microspheres exhibited more pronounced transcriptional changes over time. Taken together, these results highlight the capability of the microsphere platform for scaling up biomanufacturing of ECTs in a suspension-based culture platform.

Dataset Information

Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking.

Publications

Tunable hydrogel-microsphere composites that modulate local inflammation and collagen bulking.

Similar Datasets

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