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Hyaluronic Acid Scaffolds for Loco-Regional Therapy in Nervous System Related Disorders.

ABSTRACT: Hyaluronic acid (HA) is a Glycosaminoglycan made of disaccharide units containing N-acetyl-D-glucosamine and glucuronic acid. Its molecular mass can reach 10 MDa and its physiological properties depend on its polymeric property, polyelectrolyte feature and viscous nature. HA is a ubiquitous compound found in almost all biological tissues and fluids. So far, HA grades are produced by biotechnology processes, while in the human organism it is a major component of the extracellular matrix (ECM) in brain tissue, synovial fluid, vitreous humor, cartilage and skin. Indeed, HA is capable of forming hydrogels, polymer crosslinked networks that are very hygroscopic. Based on these considerations, we propose an overview of HA-based scaffolds developed for brain cancer treatment, central and peripheral nervous systems, discuss their relevance and identify the most successful developed systems.

SUBMITTER: Djoudi A

PROVIDER: S-EPMC9602826 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Hyaluronic Acid Scaffolds for Loco-Regional Therapy in Nervous System Related Disorders.

Djoudi Amel A Molina-Peña Rodolfo R Ferreira Natalia N Ottonelli Ilaria I Tosi Giovanni G Garcion Emmanuel E Boury Frank F

International journal of molecular sciences 20221012 20

Hyaluronic acid (HA) is a Glycosaminoglycan made of disaccharide units containing N-acetyl-D-glucosamine and glucuronic acid. Its molecular mass can reach 10 MDa and its physiological properties depend on its polymeric property, polyelectrolyte feature and viscous nature. HA is a ubiquitous compound found in almost all biological tissues and fluids. So far, HA grades are produced by biotechnology processes, while in the human organism it is a major component of the extracellular matrix (ECM) in ...[more]

PMID: 36293030

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Project description:IntroductionBiomaterials can provide localized reservoirs for controlled release of therapeutic biomolecules and drugs for applications in tissue engineering and regenerative medicine. As carriers of gene-based therapies, biomaterial scaffolds can improve efficiency and delivery-site localization of transgene expression. Controlled delivery of gene therapy vectors from scaffolds requires cell-scale macropores to facilitate rapid host cell infiltration. Recently, advanced methods have been developed to form injectable scaffolds containing cell-scale macropores. However, relative efficacy of in vivo gene delivery from scaffolds formulated using these general approaches has not been previously investigated. Using two of these methods, we fabricated scaffolds based on hyaluronic acid (HA) and compared how their unique, macroporous architectures affected their respective abilities to deliver transgenes via lentiviral vectors in vivo.MethodsThree types of scaffolds-nanoporous HA hydrogels (NP-HA), annealed HA microparticles (HA-MP) and nanoporous HA hydrogels containing protease-degradable poly(ethylene glycol) (PEG) microparticles as sacrificial porogens (PEG-MP)-were loaded with lentiviral particles encoding reporter transgenes and injected into mouse mammary fat. Scaffolds were evaluated for their ability to induce rapid infiltration of host cells and subsequent transgene expression.ResultsCell densities in scaffolds, distances into which cells penetrated scaffolds, and transgene expression levels significantly increased with delivery from HA-MP, compared to NP-HA and PEG-MP, scaffolds. Nearly 8-fold greater cell densities and up to 16-fold greater transgene expression levels were found in HA-MP, over NP-HA, scaffolds. Cell profiling revealed that within HA-MP scaffolds, macrophages (F4/80+), fibroblasts (ERTR7+) and endothelial cells (CD31+) were each present and expressed delivered transgene.ConclusionsResults demonstrate that injectable scaffolds containing cell-scale macropores in an open, interconnected architecture support rapid host cell infiltration to improve efficiency of biomaterial-mediated gene delivery.

Project description:While hyaluronic acid (HA)-based hydrogels have been used clinically for decades, the mechanisms by which HA exerts molecular weight-dependent bioactivity and how chemical modification and crosslinking may affect molecular weight-dependent bioactivity remain poorly understood. This knowledge gap presents a significant barrier to designing HA hydrogels with predictable bioactivities. As HA has been widely reported to have molecular weight-dependent effects on endothelial cells (ECs), we investigated how the molecular weight of HA in either soluble or crosslinked forms affects angiogenesis and interrogated CD44 clustering on the surface of endothelial cells as a candidate mechanism for these affects. Using soluble HA, our results show high molecular weight (HMW) HA, but not low molecular weight (LMW) HA, increased viability and tube formation in cultured human cerebral microvascular ECs (HCMVECs). No size of HA affected proliferation. When HCMVECs were cultured with crosslinked HA of varying molecular weights in the form of HA-based microporous annealed particle scaffold (HMAPS), the cell response was comparable to when cultured with soluble HA. Similarly, when implanted subcutaneously, HMAPS with HMW HA were more vascularized than those with LMW HA. We also show that antibody-mediated CD44 clustering resulted in HCMVECs with increased viability and tube-like structure formation in a manner comparable to exposure to HMW HA, suggesting that HMW acts through CD44 clustering. STATEMENT OF SIGNIFICANCE: Biomaterials based on hyaluronic acid (HA), a bioactive extracellular matrix polysaccharide, have been used in clinical products for several years. Despite the knowledge that HA molecular weight heavily influences its bioactivity, molecular weight has been largely ignored in the development of HA-based biomaterials. Given the high viscosity of high molecular weight HA typically found in native tissues, lower molecular weight polysaccharides have been used most commonly for biomaterial fabrication. By comparing the ability of injectable, microporous annealed particle scaffolds (MAPS) fabricated from variably sized HA to promote angiogenesis, this study demonstrates that MAPS with high molecular weight HA better support vascularization, likely through an unique ability to induce clustering of CD44 receptors on endothelial cells.

Project description:Heart valve disease is associated with high morbidity and mortality worldwide resulting in hundreds of thousands of heart valve replacements each year. Tissue engineered heart valves (TEHVs) have the potential to overcome the major limitations of traditional replacement valves; however, leaflet retraction has led to the failure of TEHVs in preclinical studies. As native unmodified hyaluronic acid (HA) is known to promote healthy tissue development in native heart valves, we hypothesize that adding unmodified HA to fibrin-based scaffolds common to tissue engineering will reduce retraction by increasing cell-scaffold interactions and density of the scaffolds. Using a custom high-throughput culture system, we found that incorporating HA into millimeter-scale fibrin-based cell-populated scaffolds increases initial fiber diameter and cell-scaffold interactions, causing a cascade of mechanical, morphological, and cellular responses. These changes lead to higher levels of scaffold compaction and stiffness, increased cell alignment, and less bundling of fibrin fibers by the cells during culture. These effects significantly reduce scaffold retraction and total contractile force each by around 25%. These findings increase our understanding of how HA alters tissue remodeling and could inform the design of the next generation of tissue engineered heart valves to help reduce retraction. STATEMENT OF SIGNIFICANCE: Tissue engineered heart valves (TEHVs) have the potential to overcome the major limitations of traditional replacement valves; however, leaflet retraction induced by excessive myofibroblast activation has led to failure in preclinical studies. Developing valves are rich in hyaluronic acid (HA), which helps maintain a physiological environment for tissue remodeling without retraction. We hypothesized that adding unmodified HA to TEHVs would reduce retraction by increasing cell-scaffold interactions and density of the scaffolds. Using a high-throughput tissue culture platform, we demonstrate that HA incorporation into a fibrin-based scaffold can significantly reduce tissue retraction and total contractile force by increasing fiber bundling and altering cell-mediated matrix remodeling, therefore increasing gel density and stiffness. These finding increase our knowledge of native HA's effects within the extracellular matrix, and provide a new tool for TEHV design.

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Hyaluronic Acid Scaffolds for Loco-Regional Therapy in Nervous System Related Disorders.

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Hyaluronic Acid Scaffolds for Loco-Regional Therapy in Nervous System Related Disorders.

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