Immunomodulatory contribution of mast cells to the regenerative biomaterial microenvironment.

Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex-specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later-stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile, including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials.

Preventing post-surgical cardiac adhesions with a catechol-functionalized oxime hydrogel.

Post-surgical cardiac adhesions represent a significant problem during routine cardiothoracic procedures. This fibrous tissue can impair heart function and inhibit surgical access in reoperation procedures. Here, we propose a hydrogel barrier composed of oxime crosslinked poly(ethylene glycol) (PEG) with the inclusion of a catechol (Cat) group to improve retention on the heart for pericardial adhesion prevention. This three component system is comprised of aldehyde (Ald), aminooxy (AO), and Cat functionalized PEG mixed to form the final gel (Ald-AO-Cat). Ald-AO-Cat has favorable mechanical properties, degradation kinetics, and minimal swelling, as well as superior tissue retention compared to an initial Ald-AO gel formulation. We show that the material is cytocompatible, resists cell adhesion, and led to a reduction in the severity of adhesions in an in vivo rat model. We further show feasibility in a pilot porcine study. The Ald-AO-Cat hydrogel barrier may therefore serve as a promising solution for preventing post-surgical cardiac adhesions.

Self-Assembled Colloidal Gel Using Cell Membrane-Coated Nanosponges as Building Blocks.

Colloidal gels consisting of oppositely charged nanoparticles are increasingly utilized for drug delivery and tissue engineering. Meanwhile, cell membrane-coated nanoparticles are becoming a compelling biomimetic system for innovative therapeutics. Here, we demonstrate the successful use of cell membrane-coated nanoparticles as building blocks to formulate a colloidal gel that gelates entirely based on material self-assembly without chemical cross-linking. Specifically, we prepare red blood cell membrane-coated nanosponges and mix them with an appropriate amount of cationic nanoparticles, resulting in a spontaneously formed gel-like complex. Rheological test shows that the nanosponge colloidal gel has pronounced shear-thinning property, which makes it an injectable formulation. The gel formulation not only preserves the nanosponges' toxin neutralization capability but also greatly prolongs their retention time after subcutaneous injection into mouse tissue. When tested in a mouse model of subcutaneous group A Streptococcus infection, the nanosponge colloidal gel shows significant antibacterial efficacy by markedly reducing skin lesion development. Overall, the nanosponge colloidal gel system is promising as an injectable formulation for therapeutic applications such as antivirulence treatment for local bacterial infections.

Engineering an Injectable Muscle-Specific Microenvironment for Improved Cell Delivery Using a Nanofibrous Extracellular Matrix Hydrogel.

Injection of skeletal muscle progenitors has the potential to be a minimally invasive treatment for a number of diseases that negatively affect vasculature and skeletal muscle, including peripheral artery disease. However, success with this approach has been limited because of poor transplant cell survival. This is primarily attributed to cell death due to extensional flow through the needle, the harsh ischemic environment of the host tissue, a deleterious immune cell response, and a lack of biophysical cues supporting exogenous cell viability. We show that engineering a muscle-specific microenvironment, using a nanofibrous decellularized skeletal muscle extracellular matrix hydrogel and skeletal muscle fibroblasts, improves myoblast viability and maturation in vitro. In vivo, this translates to improved cell survival and engraftment and increased perfusion as a result of increased vascularization. Our results indicate that a combinatorial delivery system, which more fully recapitulates the tissue microenvironment, can improve cell delivery to skeletal muscle.

Extracellular Matrix Hydrogel Promotes Tissue Remodeling, Arteriogenesis, and Perfusion in a Rat Hindlimb Ischemia Model.

OBJECTIVE: This study aimed to examine acellular extracellular matrix based hydrogels as potential therapies for treating peripheral artery disease (PAD). We tested the efficacy of using a tissue specific injectable hydrogel, derived from decellularized porcine skeletal muscle (SKM), compared to a new human umbilical cord derived matrix (hUC) hydrogel, which could have greater potential for tissue regeneration because of its young tissue source age. BACKGROUND: The prevalence of PAD is increasing and can lead to critical limb ischemia (CLI) with potential limb amputation. Currently there are no therapies for PAD that effectively treat all of the underlying pathologies, including reduced tissue perfusion and muscle atrophy. METHODS: In a rodent hindlimb ischemia model both hydrogels were injected 1-week post-surgery and perfusion was regularly monitored with laser speckle contrast analysis (LASCA) to 35 days post-injection. Histology and immunohistochemistry were used to assess neovascularization and muscle health. Whole transcriptome analysis was further conducted on SKM injected animals on 3 and 10 days post-injection. RESULTS: Significant improvements in hindlimb tissue perfusion and perfusion kinetics were observed with both biomaterials. End point histology indicated this was a result of arteriogenesis, rather than angiogenesis, and that the materials were biocompatible. Skeletal muscle fiber morphology analysis indicated that the muscle treated with the tissue specific, SKM hydrogel more closely matched healthy tissue morphology. Short term histology also indicated arteriogenesis rather than angiogenesis, as well as improved recruitment of skeletal muscle progenitors. Whole transcriptome analysis indicated that the SKM hydrogel caused a shift in the inflammatory response, decreased cell death, and increased blood vessel and muscle development. CONCLUSION: These results show the efficacy of an injectable ECM hydrogel alone as a potential therapy for treating patients with PAD. Our results indicate that the SKM hydrogel improved functional outcomes through stimulation of arteriogenesis and muscle progenitor cell recruitment.

Concise review: injectable biomaterials for the treatment of myocardial infarction and peripheral artery disease: translational challenges and progress.

Recently, injectable biomaterial-based therapies for cardiovascular disease have been gaining attention, because they have shown therapeutic potential in preclinical models for myocardial infarction (MI) and peripheral artery disease (PAD). Naturally derived (e.g., alginate, hyaluronic acid, collagen, or extracellular matrix-based) or synthetic (e.g., peptide or polymer-based) materials can enhance stem cell survival and retention in vivo, prolong growth factor release from bulk hydrogel or particle constructs, and even stimulate endogenous tissue regeneration as a standalone therapy. Although there are many promising preclinical examples, the therapeutic potential of biomaterial-based products for cardiovascular disease has yet to be proved on a clinical and commercial scale. This review aims to briefly summarize the latest preclinical and clinical studies on injectable biomaterial therapies for MI and PAD. Furthermore, our overall goal is to highlight the major challenges facing translation of these therapies to the clinic (e.g., regulatory, manufacturing, and delivery), with the purpose of increasing awareness of the barriers for translating novel biomaterial therapies for MI and PAD and facilitating more rapid translation of new biomaterial technologies.

Human versus porcine tissue sourcing for an injectable myocardial matrix hydrogel.

Heart failure (HF) after myocardial infarction (MI) is a leading cause of death in the western world with a critical need for new therapies. A previously developed injectable hydrogel derived from porcine myocardial matrix (PMM) has had successful results in both small and large animal MI models. In this study, we sought to evaluate the impact of tissue source on this biomaterial, specifically comparing porcine and human myocardium sources. We first developed an analogous hydrogel derived from human myocardial matrix (HMM). The biochemical and physical properties of the PMM and HMM hydrogels were then characterized, including residual dsDNA, protein content, sulfated glycosaminoglycan (sGAG) content, complex viscosity, storage and loss moduli, and nano-scale topography. Biochemical activity was investigated with in vitro studies for the proliferation of vascular cells and differentiation of human cardiomyocyte progenitor cells (hCMPCs). Next, in vivo gelation and material spread were confirmed for both PMM and HMM after intramyocardial injection. After extensive comparison, the matrices were found to be similar, yet did show some differences. Because of the rarity of collecting healthy human hearts, the increased difficulty in processing the human tissue, shifts in ECM composition due to aging, and significant patient-to-patient variability, these studies suggest that the HMM is not a viable option as a scalable product for the clinic; however, the HMM has potential as a tool for in vitro cell culture.