HA-based Scaffolds Research Articles

Systematic investigation and controlled synthesis of Ag/Ti co-doped hydroxyapatite for bone tissue engineering

Hydroxyapatite (HA) is a cornerstone bio ceramic in bone tissue engineering applications, prized for its inherent biocompatibility and structural resemblance to natural bone tissue. However, both porous and dense, conventional HA formulations face notable stability and mechanical robustness constraints, impeding their broader utility. We introduce an innovative biomaterial synthesized via a straightforward and efficient sol-gel method to surmount these challenges and imbue novel scaffolds with multifunctional capabilities. Leveraging a double doping strategy, our approach seeks to enhance mechanical performance and incorporate antibacterial features, maintaining the biocompatibility of HA-based scaffolds for advanced tissue engineering applications. In pursuit of this objective, we synthesized Ag-doped, Ag, Ti-doped, and Ti-doped HA samples to explore the impact of varying dopant types and concentrations on various structural, thermal, crystallographic, chemical, morphological, mechanical, and biocompatibility characteristics. X-ray Diffraction (XRD) analysis confirmed the presence of apatitic phase compositions across all samples, while Fourier-transform Infrared Spectroscopy (FTIR) data corroborated phosphate formation and functional group identification. Scanning Electron Microscopy (SEM) studies revealed a correlation between particle size and dopant concentration, consistent with XRD findings. Nanoindentation results indicated optimal mechanical performance was achieved with balanced incorporation of Ag and Ti ions despite increased Vickers microhardness with higher Ti concentrations. All doped samples exhibited effective antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), except for the Ti-doped HA sample. Moreover, the HA sample co-doped with equal amounts of Ag and Ti demonstrated noncytotoxicity for human lung cancer (A549) cells. In contrast, all doped samples exhibited cytotoxicity towards human prostate cancer cell (PC3) cells. Statistical analysis confirmed a synergistic enhancement of biocompatibility and mechanical performance in HA samples doped with Ag and Ti ions in equal proportions. In conclusion, our study presents a simple and effective approach for enhancing HA's mechanical and antibacterial properties through co-doping with Ag and Ti. This innovative biomaterial holds significant promise for advancing bone tissue engineering applications.

Chemical Modifications in Hyaluronic Acid-Based Electrospun Scaffolds.

Hyaluronic acid (HA) is a natural, non-sulfated glycosaminoglycan (GAG) present in ECM. It is involved in different biological functions with appealing properties in cosmetics and pharmaceutical preparations as well as in tissue engineering. Generally, HA has been electrospun in blends with natural or synthetic polymers to produce fibers having diameters in the order of nano and micro-scale whose pores can host cells able to regenerate damaged tissues. In the last decade, a rich literature on electrospun HA-based materials arose. Chemical modifications were generally introduced in HA scaffolds to favour crosslinking or conjugation with bioactive molecules. Considering the high solubility of HA in water, HA-based electrospun scaffolds are cross-linked to increase the stability in biological fluids. Crosslinking is necessary also to avoid the release of HA from the hybrid scaffold when implanted in-vivo. Furthermore, to endow the HA based scaffolds with new chemical or biological properties, conjugation of bioactive molecules to HA was widely reported. Herein, we review the existing research classifying chemical modifications on HA and HA-based electrospun fibers into three categories: i) in-situ crosslinking of electrospun HA-based scaffolds ii) off-site crosslinking of electrospun HA-based scaffolds; iii) conjugation of biofunctional molecules to HA with focus on peptides.

Low, medium, and high molecular weight hyaluronic acid effects on human dental pulp stem cells in vitro

Hyaluronic acid (HA), an extracellular biopolymer found throughout the human body, holds promise as a biocompatible and biodegradable scaffold material. High molecular weight (HMW) HA degrades, generating low molecular weight (LMW) fragments with distinct properties. These fragments can influence the behaviour of cells, including human dental pulp stem cells (hDPSCs) incorporated into HA-containing hydrogels or scaffolds. Therefore, a comprehensive examination of the impact of a range of HA molecular weights on hDPSCs is essential before designing HA-based scaffolds for these cells. hDPSC lines were cultured with LMW HA (800 Da, 1600 Da, 15 kDa), medium molecular weight HA (237 kDa), or HMW HA (1500 kDa) over six passages. The various molecular weights had negligible effects on hDPSCs viability, morphology, adhesion, or relative telomere length. Furthermore, the expression of key surface stemness markers (CD29, CD44, CD73, CD90) remained unaltered. HA did not induce osteogenic, chondrogenic, or adipogenic differentiation. Moreover, the potential for chondrogenic and osteogenic differentiation was not adversely affected by LMW or HMW HA. Various molecular weights of HA seem safe, biocompatible and therefore suitable components for hDPSCs-containing scaffolds. These findings affirm that the hDPCSs will not be negatively affected by HA fragments resulting from scaffold degradation.

Interfacial characteristics of bioglass diffusion zone between scaffold-like hydroxyapatite/wollastonite coating and dense zirconia substrate

A thin bioglass (BG) layer or diffusion zone has been used to enhance interfacial bonding between co-sintered scaffold-like micro-porous hydroxyapatite (HA) coating over dense zirconia substrate. However, there still have problems such as low fracture toughness and low wear resistance. Therefore, while meeting the basic requirements of degradability and biocompatibility, how to improve the mechanical properties of the scaffold, endow it with osteoinductivity and build a low-density porous structure has become the focus of bone scaffold research. The tri-layer bio-ceramic composites, consisting of porous HA, BG diffusion zone, and strong zirconia substrate, are designed with superior loading-bearing capability to the scaffold. Surface handling properties of the scaffold-like HA coating are further enhanced by incorporating wollastonite. The gradient in material compositions across the coating and substrate interface is further minimized by adding HA into the zirconia substrate. Benefiting from these special design and the thin BG diffusion zone, the tri-layer bio-ceramics present excellent interfacial strength, which ensures good structural strength and machinability. The results could provide the feasible options for bio-ceramic scaffolds design and manufacturing process, thus advance the practical clinical applications of HA-based scaffolds for bone repair and regeneration.

Fitness of Custom 3D-Printed Hydroxyapatite Scaffolds for Furcation Defects: A Preliminary Investigation Using Pig Jaws

<p>Abstract (Word Count: 202) Objective: This study aimed to evaluate whether 3D-printed (3DP) hydroxyapatite (HA)-based scaffolds can be customized to fit furcation defects. Materials and Methods: Two experimental degree II furcation defects were created in pig jaws, and cone-beam computed tomography (CBCT) images were taken before and after defect creation. Computer-aided design (CAD) models of scaffolds were produced by subtracting two CBCT images. For each defect, one 3DP resin block printed using a stereolithographic 3D printer served as the control, and three 3DP HA-based scaffolds were printed using an extrusion-based 3DP bioprinter. The resultant 3DP resin blocks and HA-based scaffolds were placed in the defects, and micro-CT images were taken to assess the fitness of the scaffolds. Results: Compared with the CAD models, the 3DP resin blocks and HA-based scaffolds showed approximately 90% and > 80% volume stability, respectively. Regarding the furcation defects, the linear adaptation ratio was approximately 90% for the 3DP resin blocks and > 70% for the 3DP HA-based scaffolds. The fitness of the 3DP HA-based scaffolds was inferior, with a notable depression in the central area. Conclusion: The 3DP HA-based scaffolds exhibited acceptable volume stability and fitness for the furcation defect and could be a potential strategy for promoting furcation defect regeneration.</p> <p> </p>

Bovine hydroxyapatite-based scaffold accelerated the inflammatory phase and bone growth in rats with bone defect.

Hydroxyapatite (HA) is a biomaterial widely used to treat bone defect, such as due to traffic accident. The HA scaffold is obtained from synthetic HA or natural sources, such as bovine hydroxyapatite (BHA). This study aims to compare the characteristics and in vivo performance of BHA-based and HA-based scaffolds. For this purpose, the scaffold was formulated with gelatin (GEL) and characterised by SEM-EDX, FTIR and mini autograph. The defect model was carried out on the femur area of Wistar rats classified into three animal groups: defect, HA-GEL and BHA-GEL. Postoperatively (7, 14 and 28 days), the bone was radiologically evaluated, and stained with haematoxylin-eosin, anti-CD80 and anti-CD163. The BHA-GEL scaffold showed a regular surface and spherical particle shape, whereas the HA-GEL scaffold exhibited irregular surface. The BHA-GEL scaffold had higher pore size and compressive strength and lower calcium-to-phosphorus ratio than the HA-GEL scaffold. In vivo study showed that the expression of CD80 in the three experimental groups was not significantly different. However, the expression of CD163 differed significantly between the groups. The BHA-GEL group showed robust expression of CD163 on day 7, which rapidly decreased over time. It also showed increased osteoclasts, osteoblasts and osteocytes cell count that contributed to the integrity of the defect area. In conclusion, the BHA-based scaffold exhibited the desired physical and chemical characteristics that benefit in vivo performance versus the HA-based scaffold. Thus, the BHA-based scaffold may be used as a bone graft.

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

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.

3D-Printed HA-Based Scaffolds for Bone Regeneration: Microporosity, Osteoconduction and Osteoclastic Resorption.

Additive manufacturing enables the realization of the macro- and microarchitecture of bone substitutes. The macroarchitecture is determined by the bone defect and its shape makes the implant patient specific. The preset distribution of the 3D-printed material in the macroarchitecture defines the microarchitecture. At the lower scale, the nanoarchitecture of 3D-printed scaffolds is dependent on the post-processing methodology such as the sintering temperature. However, the role of microarchitecture and nanoarchitecture of scaffolds for osteoconduction is still elusive. To address these aspects in more detail, we produced lithography-based osteoconductive scaffolds from hydroxyapatite (HA) of identical macro- and microarchitecture and varied their nanoarchitecture, such as microporosity, by increasing the maximum sintering temperatures from 1100 to 1400 °C. The different scaffold types were characterized for microporosity, compression strength, and nanoarchitecture. The in vivo results, based on a rabbit calvarial defect model showed that bony ingrowth, as a measure of osteoconduction, was independent from scaffold’s microporosity. The same applies to in vitro osteoclastic resorbability, since on all tested scaffold types, osteoclasts formed on their surfaces and resorption pits upon exposure to mature osteoclasts were visible. Thus, for wide-open porous HA-based scaffolds, a low degree of microporosity and high mechanical strength yield optimal osteoconduction and creeping substitution. Based on our study, non-unions, the major complication during demanding bone regeneration procedures, could be prevented.

Chondroitinase ABC/galectin-3 fusion proteins with hyaluronan-based hydrogels stabilize enzyme and provide targeted enzyme activity for neural applications

Objective. Chondroitinase ABC (ChABC) has emerged as a promising therapeutic agent for central nervous system regeneration. Despite multiple beneficial outcomes for regeneration, translation of this enzyme is challenged by poor pharmacokinetics, localization, and stability. Approach. This study explored the function and in vitro application of engineered ChABC fused to galectin-3 (Gal3). Two previously developed ChABC-Gal3 oligomers (monomeric and trimeric) were evaluated for functionality and kinetics, then applied to an in vitro cellular outgrowth model using dorsal root ganglia (DRGs). The fusions were combined with two formulations of hyaluronan (HA)-based scaffolds to determine the extent of active enzyme release compared to wild type (WT) ChABC. Main Results. Monomeric and trimeric ChABC-Gal3 maintained digestive capabilities with kinetic properties that were substrate-dependent for chondroitin sulfates A, B, and C. The fusions had longer half-lives at 37 °C on the order of seven fold for monomer and twelve fold for trimer compared to WT. Both fusions were also effective at restoring DRG outgrowth in vitro. To create a combination approach, two triple-component hydrogels containing modified HA were formulated to match the mechanical properties of native spinal cord tissue and to support astrocyte viability (>80%) and adhesion. The hydrogels included collagen-I and laminin mixed with either 5 mg ml−1 of glycidyl methacrylate HA or 3 mg ml−1 Hystem. When combined with scaffolds, ChABC-Gal3 release time was lengthened compared to WT. Both fusions had measurable enzymatic activity for at least 10 d when incorporated in gels, compared to WT that lost activity after 1 d. These longer term release products from gels maintained adequate function to promote DRG outgrowth. Significance. Results of this study demonstrated cohesive benefits of two stabilized ChABC-Gal3 oligomers in combination with HA-based scaffolds for neural applications. Significant improvements to ChABC stability and release were achieved, meriting future studies of ChABC-Gal3/hydrogel combinations to target neural regeneration.

Oxi-HA/ADH Hydrogels: A Novel Approach in Tissue Engineering and Regenerative Medicine

Hyaluronic acid (HA) is a natural polyelectrolyte abundant in mammalian connective tissues, such as cartilage and skin. Both endogenous and exogenous HA produced by fermentation have similar physicochemical, rheological, and biological properties, leading to medical and dermo-cosmetic products. Chemical modifications such as cross-linking or conjugation in target groups of the HA molecule improve its properties and in vivo stability, expanding its applications. Currently, HA-based scaffolds and matrices are of great interest in tissue engineering and regenerative medicine. However, the partial oxidation of the proximal hydroxyl groups in HA to electrophilic aldehydes mediated by periodate is still rarely investigated. The introduced aldehyde groups in the HA backbone allow spontaneous cross-linking with adipic dihydrazide (ADH), thermosensitivity, and noncytotoxicity to the hydrogels, which are advantageous for medical applications. This review provides an overview of the physicochemical properties of HA and its usual chemical modifications to better understand oxi-HA/ADH hydrogels, their functional properties modulated by the oxidation degree and ADH concentration, and the current clinical research. Finally, it discusses the development of biomaterials based on oxi-HA/ADH as a novel approach in tissue engineering and regenerative medicine.

Cobalt content modulates characteristics and osteogenic properties of cobalt-containing hydroxyapatite in in-vitro milieu

To develop an efficient scaffold for bone tissue engineering application, the influence of cobalt ion as generator of a hypoxia-like response was examined on cobalt-containing hydroxyapatite (Co-HA) scaffold properties and cultured osteoblast-like cell behavior. FTIR and XRD spectra, as well as EDX analysis and elemental mapping, showed successful cobalt doping as well as the formation of cobalt-based compounds on the surface of HA particles. Metabolic activities of cultured MG-63 cells in the presence of the Co-HA scaffold also showed a fluctuation with increasing cobalt content and revealed maximum osteoblastic cell activity accompanied by a considerable apoptotic cell reduction when the cobalt content in HA reached to 1.25 % (LCo-HA). The results showed the cobalt content of more than 1.25 % in the Co-HA scaffold which results the cobalt concentrations of more than 12 ppm in culture medium may cause cytotoxic effect on osteoblastic metabolic activities on the scaffold. The apatite growth was also observed on the LCo-HA scaffold in simulated body fluid. Alkaline phosphatase activity and calcium deposition of the osteoblastic cells cultured on the LCo-HA scaffold also coincided with the results of characterization and cytotoxicity as compared to the HA scaffold and control sample. The results demonstrated that cobalt improves osteogenic properties of HA-based scaffolds, and the LCo-HA derivative with 1.25 % cobalt content can be considered as a potential cobalt-containing HA scaffold for use in bone tissue engineering.

Three-Dimensional Printing of Hydroxyapatite Composites for Biomedical Application

Hydroxyapatite (HA) and HA-based nanocomposites have been recognized as ideal biomaterials in hard tissue engineering because of their compositional similarity to bioapatite. However, the traditional HA-based nanocomposites fabrication techniques still limit the utilization of HA in bone, cartilage, dental, applications, and other fields. In recent years, three-dimensional (3D) printing has been shown to provide a fast, precise, controllable, and scalable fabrication approach for the synthesis of HA-based scaffolds. This review therefore explores available 3D printing technologies for the preparation of porous HA-based nanocomposites. In the present review, different 3D printed HA-based scaffolds composited with natural polymers and/or synthetic polymers are discussed. Furthermore, the desired properties of HA-based composites via 3D printing such as porosity, mechanical properties, biodegradability, and antibacterial properties are extensively explored. Lastly, the applications and the next generation of HA-based nanocomposites for tissue engineering are discussed.

Bioceramic hydroxyapatite-based scaffold with a porous structure using honeycomb as a natural polymeric Porogen for bone tissue engineering

BackgroundThe application of bioceramic hydroxyapatite (HA) derived from materials high in calcium to tissue engineering has been of concern, namely scaffold. Scaffold pores allow for cell mobility metabolic processes, and delivery of oxygen and nutrients by blood vessel. Thus, pore architecture affects cell seeding efficiency, cell viability, migration, morphology, cell proliferation, cell differentiation, angiogenesis, mechanical strength of scaffolds, and, eventually, bone formation. Therefore, to improve the efficacy of bone regeneration, several important parameters of the pore architecture of scaffolds must be carefully controlled, including pore size, geometry, orientation, uniformity, interconnectivity, and porosity, which are interrelated and whose coordination affects the effectiveness of bone tissue engineering. The honeycomb (HCB) as natural polymeric porogen is used to pore forming agent of scaffolds. It is unique for fully interconnected and oriented pores of uniform size and high mechanical strength in the direction of the pores. The aim of this study was therefore to evaluate the effect of HCB concentration on macropore structure of the scaffolds.MethodsBioceramic hydroxyapatite (HA) was synthesized from abalone mussel shells (Halioitis asinina) using a precipitation method, and HA-based scaffolds were fabricated with honeycomb (HCB) as the porogen agent. Pore structure engineering was successfully carried out using HCB at concentrations of 10, 20, and 30 wt%.ResultsThe Energy Dispersive X-Ray Spectroscopy (EDS) analysis revealed that the Ca/P molar ratio of HA was 1.67 (the stoichiometric ratio of HA). The Fourier Transform Infrared Spectroscopy (FTIR) spectra results for porous HA-based scaffolds and synthesized HA showed that no chemical decomposition occurred in the HA-based scaffold fabrication process. The porosity of the scaffold tended to increase when higher concentrations of HCB were added. XRD data show that the HCB was completely degraded from the scaffold material. The cell metabolic activity and morphology of the HA + HCB 30 wt% scaffold enable it to facilitate the attachment of MC3T3E1 cells on its surface.ConclusionHCB 30 wt% is the best concentration to fabricate the scaffold corresponding to the criteria for pores structure, crystallographic properties, chemical decomposition process and cell viability for bone tissue engineering.

Functionalization of hyaluronic acid hydrogels with ECM-derived peptides to control myoblast behavior

Volumetric muscle loss (VML) occurs when skeletal muscle injury is too large for the body to fully self-repair. Typically, fibrotic tissue fills the void, which reduces muscle functionality and limb movement. Although a wide variety of natural and synthetic scaffolds have been studied with the purpose of providing the appropriate structural support, to date no scaffold has significantly restored muscle functionality after VML. Satellite cells, adult stem cells within the muscle capable of restoring smaller injuries, are sensitive to the stiffness and composition of the surrounding environment. Scaffolds that only address structural support are not sufficient to restore functionality and instead need to be designed to both promote satellite cell activation and prevent excessive fibroblast recruitment. The objective of this study was to design a scaffold that mimicked the regenerative environment and determine how the biomechanical properties differentially influence myogenic precursor and connective tissue cells. One of the main extracellular matrix (ECM) molecules upregulated during regeneration is hyaluronic acid (HA). Therefore, thiol-modified HA and poly(ethylene glycol) diacrylate hydrogels were generated and functionalized with peptides based on ECM known to influence regeneration, including fibronectin, laminin and tenascin-C. Scaffolds with different stiffness were created by varying HA content. The influence of HA stiffness and peptide functionalization on myogenic precursor and connective tissue cell proliferation, migration and gene expression was quantified. Our results indicated that HA hydrogels functionalized with the laminin peptide, IKVAV, show potential due to the enhanced promotion of myogenic cell behaviors including migration, proliferation and an increase in relevant transcription factors. Statement of SignificanceThe goal of this study was to identify hyaluronic acid (HA) hydrogels with peptide and stiffness combinations that will direct muscle-derived cells towards regenerating phenotypes. While the interaction of skeletal muscle with RGD-functionalized HA hydrogels has been investigated, none of the other peptides described in this study had been used in the context of HA-based scaffolds and skeletal muscle-derived cells. Notably, the response of cells to variations in mechanics was dependent on ECM coating and lineage. The 3% HA functionalized with the laminin peptide, IKVAV, showed the most promise for future in vivo studies, as these hydrogels best promoted myoblast cell proliferation, attachment and spreading, enhanced migration over connective tissue cells and upregulated transcription factors associated with activated satellite cells.

Electrospinning in water and in situ crosslinking of hyaluronic acid / cyclodextrin nanofibers: Towards wound dressing with controlled drug release

Hyaluronic acid (HA) is widely investigated due to its high potential for wound dressing applications. The fabrication of biomimetic HA-based scaffolds by electrospinning is thus extensively studied. However, HA is often dissolved in toxic organic solvents to allow the efficient production of electrospun nanofibers. Indeed, although HA is soluble in water, its ionic nature leading to long-range electrostatic interactions and the presence of counter ions induce a dramatic increase of the viscosity of aqueous HA solutions without insuring enough chain entanglements necessary for a stable and efficient electrospinning. In this study, biocompatible insoluble HA-based nanofibers were fabricated by electrospinning in pure water. To this end, poly(vinyl alcohol) (PVA) was added as a carrier polymer and it was found that the addition of hydroxypropyl-βcyclodextrin (HPβCD) stabilized the process of electrospinning and led to the efficient formation of uniform nanofibrous scaffolds. An in situ crosslinking process of the scaffolds is also proposed, insuring a whole fabrication process without any toxicity. Furthermore, the beneficial presence of HPβCD in the HA-based scaffolds paves the way for wound dressing applications with controlled drug encapsulation-release properties. As a proof of concept, naproxen (NAP), a non-steroidal anti-inflammatory drug was chosen as a model drug. NAP was impregnated into the scaffolds either in aqueous solution or under supercritical CO2. The resulting functional scaffolds showed a regular drug release profile along several days without losing the fibrous structure. This study proposes a simple approach to form stable HA-based nanofibrous scaffolds embedding HPβCD using water as the only solvent, enabling the development of safe functional wound dressings.

The effect of hyaluronan on the motility of skin dermal fibroblasts in nanofibrous scaffolds

Nanofibrous scaffolds that use the native extracellular matrix are promising developments in skin tissue regeneration because they provide the proper environment for the adhesion, migration and growth of skin dermal fibroblasts, important during wound healing. In this study, we focus on hyaluronan as a native ECM that regulates cellular motility in nanofibrous scaffolds. PCL/HA nanofibrous scaffolds were generated by electrospinning and assessed for various physicochemical properties. HA-based scaffolds significantly enhanced cell infiltration in vitro and in vivo. The observation of movements in living cells revealed that HA-based scaffolds regulated cell migration speed and direction. This phenomenon may influences by the variation in cell adhesion receptors-integrin β1, and vinculin formation and distribution. Furthermore, we confirmed that HA/CD44 interactions can activate the TGF-β/MMP-2 signaling pathway that promotes cell motility. These findings suggest HA functions in the cell motility of nanofibrous scaffolds and have potential implications for the use of HA-based scaffolds in skin tissue regeneration applications.

Hyaluronan and cardiac regeneration.

Hyaluronan (HA) is abundantly expressed in several human tissues and a variety of roles for HA has been highlighted. Particularly relevant for tissue repair, HA is actively produced during tissue injury, as widely evidenced in wound healing investigations. In the heart HA is involved in physiological functions, such as cardiac development during embryogenesis, and in pathological conditions including atherosclerosis and myocardial infarction. Moreover, owing to its relevant biological properties, HA has been widely used as a biomaterial for heart regeneration after a myocardial infarction. Indeed, HA and its derivatives are biodegradable and biocompatible, promote faster healing of injured tissues, and support cells in relevant processes including survival, proliferation, and differentiation. Injectable HA-based therapies for cardiovascular disease are gaining growing attention because of the benefits obtained in preclinical models of myocardial infarction. HA-based hydrogels, especially as a vehicle for stem cells, have been demonstrated to improve the process of cardiac repair by stimulating angiogenesis, reducing inflammation, and supporting local and grafted cells in their reparative functions. Solid-state HA-based scaffolds have been also investigated to produce constructs hosting mesenchymal stem cells or endothelial progenitor cells to be transplanted onto the infarcted surface of the heart. Finally, applying an ex-vivo mechanical stretching, stem cells grown in HA-based 3D scaffolds can further increase extracellular matrix production and proneness to differentiate into muscle phenotypes, thus suggesting a potential strategy to create a suitable engineered myocardial tissue for cardiac regeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0100-4) contains supplementary material, which is available to authorized users.

Hyaluronic acid-based scaffold for central neural tissue engineering.

Central nervous system (CNS) regeneration with central neuronal connections and restoration of synaptic connections has been a long-standing worldwide problem and, to date, no effective clinical therapies are widely accepted for CNS injuries. The limited regenerative capacity of the CNS results from the growth-inhibitory environment that impedes the regrowth of axons. Central neural tissue engineering has attracted extensive attention from multi-disciplinary scientists in recent years, and many studies have been carried out to develop cell- and regeneration-activating biomaterial scaffolds that create an artificial micro-environment suitable for axonal regeneration. Among all the biomaterials, hyaluronic acid (HA) is a promising candidate for central neural tissue engineering because of its unique physico-chemical and biological properties. This review attempts to outline current biomaterials-based strategies for CNS regeneration from a tissue engineering point of view and discusses the main progresses in research of HA-based scaffolds for central neural tissue engineering in detail.

The use of hyaluronan to regulate protein adsorption and cell infiltration in nanofibrous scaffolds

Electrospun nanofibers are prepared with mixtures of natural and synthetic polymers that can behave cooperatively to demonstrate combinations of mechanical, structural and biochemical properties for tissue engineering applications. However, the large surface area and inherent small pores of these structures give nanofibrous scaffolds high non-specific protein adsorption and poor cell infiltration. In this study, we developed a protein resistant and porous nanofibrous scaffold composed of hyaluronan (HA), silk fibroin (SF), and polycaprolactone (PCL) blends via one-step emulsion electrospinning. The scaffolds were characterized and evaluated for nanostructures, chemical composition, mechanical properties, hydrophilicity, and protein adsorption. Swelling and degradation studies revealed the formation of oriented pore structures within the body of the scaffolds and increasing the pore size between fibers. Addition of HA component transformed current PCL/SF components into hydrophilic fibers, which caused the suppression of non-specific protein adsorption, resulting in the reduction of fibrosis tissue thickness and macrophages adhesion in vivo. Importantly, HA-based scaffolds significantly enhanced cell infiltration in vitro and tissue ingrowth in vivo. In vitro cultivation of human primary skin fibroblasts on the HA-based scaffolds showed a significant increase in cell proliferation and filopodia protrusions, but decreased in collagen I production. Furthermore, HA and HA-based scaffolds interacted with cell surface receptor CD44 to activate TGF-β1/MMPs signaling pathways that conducive to cell migration. These findings suggest that such an HA-based nanofibrous scaffold resists protein adsorption and enhances cell infiltration, may offer possibilities to overcome the limitations of electrospinning technology.

Fibronectin–hyaluronic acid composite hydrogels for three-dimensional endothelial cell culture

Biomaterials that actively promote both wound healing and angiogenesis are of critical importance for many biomedical applications, including tissue engineering. In particular, hyaluronic acid (HA) is an important player that has multiple roles throughout the angiogenic process in the body. Previously, our laboratory has developed photocrosslinkable HA-based scaffolds that promote angiogenesis when implanted in vivo. This paper reports the incorporation of a photocrosslinkable fibronectin (FN) conjugate into three-dimensional (3-D) HA hydrogel networks to enhance endothelial cell adhesion and angiogenesis. The results demonstrate significantly better retention of FN that was photocrosslinked within HA hydrogels compared to FN that was physically adsorbed within HA hydrogels. Increased viability of endothelial cells cultured in 3-D HA hydrogels with photoimmobilized FN, compared to adsorbed FN, was also observed. Endothelial cells were cultured within hydrogels for up to 6 days, a period over which cell proliferation, migration and an angiogenic phenotype were influenced by varying the concentration of incorporated FN. The results demonstrate the potential of these composite hydrogels as biomaterial scaffolds capable of promoting wound healing and angiogenesis.