Hydrogels For Regenerative Medicine Research Articles

Use of Hydrogels in Regenerative Medicine: Focus on Mechanical Properties

Use of Hydrogels in Regenerative Medicine: Focus on Mechanical Properties

Methods to achieve tissue-mimetic physicochemical properties in hydrogels for regenerative medicine and tissue engineering.

Hydrogels are water-swollen polymeric matrices with properties that are remarkably similar in function to the extracellular matrix. For example, the polymer matrix provides structural support and adhesion sites for cells in much of the same way as the fibers of the extracellular matrix. In addition, depending on the polymer used, bioactive sites on the polymer may provide signals to initiate certain cell behavior. However, despite their potential as biomaterials for tissue engineering and regenerative medicine applications, fabricating hydrogels that truly mimic the physicochemical properties of the extracellular matrix to physiologically-relevant values is a challenge. Recent efforts in the field have sought to improve the physicochemical properties of hydrogels using advanced materials science and engineering methods. In this review, we highlight some of the most promising methods, including crosslinking strategies and manufacturing approaches such as 3D bioprinting and granular hydrogels. We also provide a brief perspective on the future outlook of this field and how these methods may lead to the clinical translation of hydrogel biomaterials for tissue engineering and regenerative medicine applications.

Gelatin-Based Scaffolds with Carrageenan and Chitosan for Soft Tissue Regeneration.

Motivated by the enormous potential of hydrogels in regenerative medicine, new biocompatible gelatin-based hybrid hydrogels were developed through a green process using poly(ethylene glycol) diglycidyl ether as a cross-linking agent, adding carrageenan and chitosan polysaccharides to the network to better mimic the hybrid composition of native extracellular matrix. Overall, the hydrogels show suitable structural stability, high porosity and pore interconnectivity, good swellability, and finally, biocompatibility. Their mechanical behavior, investigated by tensile and compression tests, appears to be characterized by nonlinear elasticity with high compliance values, fast stress-relaxation, and good strain reversibility with no sign of mechanical failure for compressive loading-unloading cycles at relatively high deformation levels of 50%. Degradation tests confirm the hydrogel bioresorbability by gradual hydrolysis, during which the structural integrity of both materials is maintained, while their mechanical behavior becomes more and more compliant. Human Umbilical Cord-derived Mesenchymal Stem Cells (hUC-MSCs) were used to test the hydrogels as potential carriers for cell delivery in tissue engineering. hUC-MSCs cultured inside the hydrogels show a homogenous distribution and maintain their growth and viability for at least 21 days of culture, with an increasing proliferation trend. Hence, this study contributes to a further understanding of the potential use of hybrid hydrogels and hUC-MSCs for a wide range of biomedical applications, particularly in soft tissue engineering.

Human Hair Keratin-Based Hydrogels in Regenerative Medicine: Current Status and Future Directions.

Regenerative medicine (RM) is a multidisciplinary field that utilizes the inherent regenerative potential of human cells to generate functionally and physiologically acceptable human cells, tissues, and organs in vivo or ex vivo. An appropriate biomaterial scaffold with desired physicochemical properties constitutes an important component of a successful RM approach. Among various forms of biomaterials explored until the present day, hydrogels have emerged as a versatile candidate for tissue engineering and regenerative medicine (TERM) applications such as scaffolds for spatial patterning and delivering therapeutic agents, or substrates to enhance cell growth, differentiation, and migration. Although hydrogels can be prepared from a variety of synthetic polymers as well as biopolymers, the latter are preferred for their inherent biocompatibility. Specifically, keratins are fibrous proteins that have been recently explored for constructing hydrogels useful for RM purposes. The present review discusses the suitability of keratin-based biomaterials in RM, with a particular focus on human hair keratin hydrogels and their use in various RM applications.

Self-Assembled Peptide Hydrogels in Regenerative Medicine.

Regenerative medicine is a complex discipline that is becoming a hot research topic. Skin, bone, and nerve regeneration dominate current treatments in regenerative medicine. A new type of drug is urgently needed for their treatment due to their high vulnerability to damage and weak self-repairing ability. A self-assembled peptide hydrogel is a good scaffolding material in regenerative medicine because it is similar to the cytoplasmic matrix environment; it promotes cell adhesion, migration, proliferation, and division; and its degradation products are natural and harmless proteins. However, fewer studies have examined the specific mechanisms of self-assembled peptide hydrogels in promoting tissue regeneration. This review summarizes the applications and mechanisms of self-assembled short peptide and peptide hydrogels in skin, bone, and neural healing to improve their applications in tissue healing and regeneration.

Nanocomposite Hydrogels in Regenerative Medicine: Applications and Challenges.

Regenerative medicine is a highly regarded multidisciplinary field that aims to transform the future of clinical medicine through curative strategies rather than palliative therapies. As an emerging field, the development of regenerative medicine cannot be achieved without multifunctional biomaterials. Among the various bioscaffold materials, hydrogels are one of the materials of interest in bioengineering and medical research because of their similarity to the natural extracellular matrix and good biocompatibility. However, conventional hydrogels have simple internal structures and single cross-linking modes, which require improvement in a single function and structural stability. Introducing multifunctional nanomaterials into 3D hydrogel networks physically or chemically avoids their disadvantages. Nanomaterials (NMs) are materials in the size range of 1-100nm with distinct physical and chemical properties that differ from that of the macroscopic size and enable hydrogels to exhibit multifunctionality. Although regenerative medicine and hydrogels have been well researched in their respective fields, the connection between nanocomposite hydrogels (NCHs) and regenerative medicine has not been elaborated. Therefore, this review briefly describes the preparation and design requirements of NCHs and discusses their applications and challenges in regenerative medicine, hoping to clarify the relationship between the two.

PBP‐based bioprinting of hydrogels for biomedical applications

AbstractThree‐dimensional (3D) printing of hydrogels to form complex structures has been widely used in tissue engineering. Projection‐based 3D printing (PBP) has faster printing, lower cell damage, and higher printing resolution compared with other 3D printing methods, providing a potential strategy for printing elaborate 3D hydrogel structures. In this review, we introduced the composition and printing process of PBP. We then discuss the study of hydrogels for PBP, including chemical structure modification and property optimization. More importantly, we highlight the potential applications of PBP‐based hydrogels in regenerative medicine and tissue engineering, and discuss the current challenges and future prospects of PBP‐based hydrogels. Ideas are provided for the study of PBP, hydrogel bioinks, and related fields.

Biofunctionalization of hydrogel-based scaffolds for vascular tissue regeneration

Congenital and acquired tissular losses due to disease or trauma are a major world health problem. Regenerative therapy aims to fix damaged tissues by directing the natural capacity of a host organism to use biofunctionalized artificial tissue scaffolds. These three-dimensional (3D) scaffolds can be customized with cells and/or bioactive molecules to induce cellular homing and angiogenesis, essential to ensure successful tissue regeneration. Hydrogels (HGs) scaffolds are networks of hydrophilic homopolymers, copolymers, and/or macromers with chemical and biological activities that enhance their cell colonization. The use of HGs in regenerative medicine has shown to be advantageous since HGs can be prepared under clinical-grade conditions and tailored to the specific needs of the replaced tissue. They can be made to emulate native extracellular matrices (ECMs) including physical, mechanical, and chemical cues and resilience properties. These customized HGs can reproduce the natural hygroscopic capacity of the original tissue which improves cellular anchoring, nutrition, and waste disposal. They can enable host molecular and cellular modification conducive to a natural cellular microenvironment, modifying the properties of the scaffold, and improving chemotaxis, cell adhesion, migration, proliferation, differentiation, and angiogenesis; HGs can be created and biofunctionalized with linked growth factors and synthetic peptides tailored to positively influence scaffold colonization and functional biocompatibility. This review aims to collect the most relevant information regarding biofunctionalization of HGs used for vascular tissue regeneration, their biological effects, and their clinical implications. While most biofunctionalized HGs are still under investigation, some of them have been studied in vitro, ex vivo, and in vivo with promising results. In this regard, in vivo studies have shown that biofunctionalized scaffolds with peptides such as chitosan hydrogel with LL-37 promotes angiogenesis and healing of pressure ulcers. Also, the GHK tripeptide is widely used in trials focused on guided tissue remodeling.

Hybrid 3D Printing of Advanced Hydrogel-Based Wound Dressings with Tailorable Properties.

Despite the extensive utilization of polysaccharide hydrogels in regenerative medicine, current fabrication methods fail to produce mechanically stable scaffolds using only hydrogels. The recently developed hybrid extrusion-based bioprinting process promises to resolve these current issues by facilitating the simultaneous printing of stiff thermoplastic polymers and softer hydrogels at different temperatures. Using layer-by-layer deposition, mechanically advantageous scaffolds can be produced by integrating the softer hydrogel matrix into a stiffer synthetic framework. This work demonstrates the fabrication of hybrid hydrogel-thermoplastic polymer scaffolds with tunable structural and chemical properties for applications in tissue engineering and regenerative medicine. Through an alternating deposition of polycaprolactone and alginate/carboxymethylcellulose gel strands, scaffolds with the desired architecture (e.g., filament thickness, pore size, macro-/microporosity), and rheological characteristics (e.g., swelling capacity, degradation rate, and wettability) were prepared. The hybrid fabrication approach allows the fine-tuning of wettability (approx. 50–75°), swelling (approx. 0–20× increased mass), degradability (approx. 2–30+ days), and mechanical strength (approx. 0.2–11 MPa) in the range between pure hydrogels and pure thermoplastic polymers, while providing a gradient of surface properties and good biocompatibility. The controlled degradability and permeability of the hydrogel component may also enable controlled drug delivery. Our work shows that the novel hybrid hydrogel-thermoplastic scaffolds with adjustable characteristics have immense potential for tissue engineering and can serve as templates for developing novel wound dressings.

Tough Double Network Hydrogel and Its Biomedical Applications.

Soft and wet hydrogels have many similarities to biological tissues, though their mechanical fragility had been one of the biggest obstacles in biomedical applications. Studies and developments in double network (DN) hydrogels have elucidated how to create tough gels universally based on sacrificial bond principles and opened a path for biomedical application of hydrogels in regenerative medicine and artificial soft connective tissues, such as cartilage, tendon, and ligament, which endure high tension and compression. This review explores a universal toughening mechanism for and biomedical studies of DN hydrogels. Moreover, because the term sacrificial bonds has been mentioned often in studies of bone tissues, consisting of biomacromolecules and biominerals, recent studies of gel-biomineral composites to understand early-stage osteogenesis and to simulate bony sacrificial bonds are also summarized.

Entanglement-Driven Adhesion, Self-Healing, and High Stretchability of Double-Network PEG-Based Hydrogels.

Hydrogels that are capable of wet adhesion and self-healing can enable major advances in a variety of biomedical applications such as tissue regeneration, wound dressings, wearable/implantable devices, and drug delivery. We hereby developed an innovative but simple strategy to achieve adhesive, self-healing, and highly stretchable double-network hydrogels, which were composed of a primary covalent polyethylene glycol diacrylate (PEGDA) network in combination with a noncovalent network of highly diffusive, giant PEG chains. The adhesion to substrates including tissue matrices was instant and repeatable due to the diffusive PEG chains that can spontaneously penetrate and entangle with the substrate network. Combining the intrinsic biocompatibility of PEG and rational design for tuning the hydrogel network properties, we exemplarily demonstrated that this hydrogel can be used as a three-dimensional matrix for cell culture or as a tissue adhesive for wound healing. The in vivo study showed that the hydrogel is capable of effectively triggering skin wound healing with a significantly lower immune response in comparison to commercial tissue adhesives currently used in clinics. Therefore, our study provides new and critical insights into the design strategy to achieve adhesion and rehealability by taking advantages of the entanglement effect from double-network hydrogels and opens up a new avenue for the application of entanglement-driven hydrogels in regenerative medicine.

Magnetothermal heating facilitates the cryogenic recovery of stem cell-laden alginate-Fe3O4 nanocomposite hydrogels.

Constructs of magnetic nanocomposite hydrogels microencapsulated with stem cells are of great interest as smart materials for tissue engineering and regenerative medicine. Due to the short shelf life of such biocomposites at an ambient temperature, their long-term storage and banking at cryogenic temperatures are essential for the "off-the-shelf" availability of such biocomposites for widespread clinical applications. However, high-quality cryogenic recovery of stem cell-nanocomposite hydrogel constructs has not yet been achieved due to the damage to cells and/or microstructures of hydrogel constructs caused by ice formation, particularly during warming from cryogenic temperatures. Herein, stem cell-magnetic nanocomposite hydrogel constructs, which have an inherent magnetothermal property provided by embedded magnetic nanoparticles, are explored to achieve ultra-rapid cryogenic warming. The binding of water molecules by the hydrogel combined with the magnetothermal heating greatly suppressed ice formation during both cryogenic cooling and warming. Thus, the cryogenic recovery of nanocomposite hydrogel constructs with intact microstructures and fully functional stem cells from ultra-low temperatures was successfully achieved. We further demonstrated that magnetic nanocomposite hydrogels microencapsulated with stem cells could be conveniently manipulated for a self-assembled 3D culture. Together, we have developed a highly efficient and easy-to-perform approach for the cryogenic recovery of stem cell-encapsulated magnetic nanocomposite hydrogel constructs. Our results will facilitate the applications of such stem cell-magnetic nanocomposite hydrogels in regenerative medicine and tissue engineering.

The bio in the ink: cartilage regeneration with bioprintable hydrogels and articular cartilage-derived progenitor cells.

Despite its limited ability to repair, articular cartilage harbors an endogenous population of progenitor cells (ACPCs), that to date, received limited attention in biomaterials and tissue engineering applications. Harnessing the potential of these cells in 3D hydrogels can open new avenues for biomaterial-based regenerative therapies, especially with advanced biofabrication technologies (e.g. bioprinting). This study highlights the potential of ACPCs to generate neo-cartilage in a gelatin-based hydrogel and bioink. The ACPC-laden hydrogel is a suitable substrate for chondrogenesis and data shows it has a bias in directing cells towards a superficial zone phenotype. For the first time, ACPC-hydrogels are evaluated both as alternative for and in combination with chondrocytes and MSCs, using co-cultures and bioprinting for cartilage regeneration in vitro. This study provides important cues on ACPCs, indicating they represent a promising cell source for the next generation of cartilage constructs with increased biomimicry.

25th anniversary article: Rational design and applications of hydrogels in regenerative medicine.

Hydrogels are hydrophilic polymer-based materials with high water content and physical characteristics that resemble the native extracellular matrix. Because of their remarkable properties, hydrogel systems are used for a wide range of biomedical applications, such as three-dimensional (3D) matrices for tissue engineering, drug-delivery vehicles, composite biomaterials, and as injectable fillers in minimally invasive surgeries. In addition, the rational design of hydrogels with controlled physical and biological properties can be used to modulate cellular functionality and tissue morphogenesis. Here, the development of advanced hydrogels with tunable physiochemical properties is highlighted, with particular emphasis on elastomeric, light-sensitive, composite, and shape-memory hydrogels. Emerging technologies developed over the past decade to control hydrogel architecture are also discussed and a number of potential applications and challenges in the utilization of hydrogels in regenerative medicine are reviewed. It is anticipated that the continued development of sophisticated hydrogels will result in clinical applications that will improve patient care and quality of life.

Hydrogels in Regenerative Medicine: Towards Understanding Structure–Function Relationships

Hydrogels are playing an increasing role in regenerative medicine owing to their growing functional sophistication. This is being underpinned by advances in hydrogel synthesis, particularly through molecular and genetic engineering, which provide greater control of hydrogel structure and hence the emergence of hydrogels with new functionalities. In order to exploit this capability it is necessary to fully understand the relationship between hydrogel structure and function. This article will investigate the nature of hydrogel-structure relationships by: highlighting the key attributes of hydrogels that modulate their function, discussing the link between these attributes and hydrogel behavior, and identifying possible measurement strategies to elucidate them.