Hydrogels as Scaffolds in Bone-Related Tissue Engineering and Regeneration

Several years have passed since the medical and scientific communities leaned toward tissue engineering as the most promising field to aid bone diseases and defects resulting from degenerative conditions or trauma. Owing to their histocompatibility and non-immunogenicity, bone grafts, precisely autografts, have long been the gold standard in bone tissue therapies. However, due to issues associated with grafting, especially the surgical risks and soaring prices of the procedures, alternatives are being extensively sought and researched. Fibrous and non-fibrous materials, synthetic substitutes, or cell-based products are just a few examples of research directions explored as potential solutions. A very promising subgroup of these replacements involves hydrogels. Biomaterials resembling the bone extracellular matrix and therefore acting as 3D scaffolds, providing the appropriate mechanical support and basis for cell growth and tissue regeneration. Additional possibility of using various stimuli in the form of growth factors, cells, etc., within the hydrogel structure, extends their use as bioactive agent delivery platforms and acts in favor of their further directed development. The aim of this review is to bring the reader closer to the fascinating subject of hydrogel scaffolds and present the potential of these materials, applied in bone and cartilage tissue engineering and regeneration.     

Bone‐guided regeneration: from inert biomaterials to bioactive polymer (nano)composites

Natural bone is a unique nanostructured material made of collagen fibre matrix and hydroxyapatite (HA) nanocrystals, providing mechanical support and protection from the vertebrate skeleton. However, in severe cases like bone‐deficiencies, bone needs to be “externally” repaired. Initially, different biological solutions were developed in bone‐guided regeneration. However, due to the limitations with the existing biological grafts, a lot of researches have been devoted toward biomaterials including metals, ceramics, and polymers. On the basis of the interface reactions between the implant and the surrounding tissues, these biomaterials may be classified as “nearly inert” or bioactive. Interestingly, the bioactive materials exhibit a specific biological response, leading to the formation of a natural bonding junction between the bone and the implant during bone regeneration. Recently, a special attention has been paid to a new generation of bioactive materials, i.e. (nano)structured biomaterials composed of a bioresorbable polymer matrix reinforced with bioactive inorganic compounds. While (bio)ceramic component provides the bioactivity, these materials can be readily engineered in such a way that their resorption rate in the body match the formation rate of the new tissue. This review hence reports the different biological and non‐biological solutions developed in bone‐guided regeneration, with a special emphasis on polymer‐based materials, and our recent results obtained in osseointegration The bone physiology, and its natural regeneration are also described. Copyright © 2011 John Wiley & Sons, Ltd.     

Laponite–Gelatin Nanofibrous Microsphere Promoting Human Dental Follicle Stem Cells Attachment and Osteogenic Differentiation for Noninvasive Stem Cell Transplantation

Nanofibrous microspheres (NFM) are emerging as prominent next-generation biomimetic injectable scaffold system for stem cell delivery and different tissue regeneration where nanofibrous topography facilitates ECM-like stem cells niches. Addition of osteogenic bioactive nanosilicate platelets within NFM can provide osteoconductive cues to facilitate matrix mediated osteogenic differentiation of stem cells and enhance the efficiency of bone tissue regeneration. In this study, gelatin nanofibrous microspheres are prepared containing fluoride-doped laponite XL21 (LP) using the emulsion mediated thermal induce phase separation (TIPS) technique. Systematic studies are performed to understand the effect of physicochemical properties of biomimicking NFM alone and with different concentrations of LP on human dental follicle stem cells (hDFSCs), their cellular attachment, proliferation, and osteogenic differentiation. The study highlights the effect of LP nanosilicate with biomimicking nanofibrous injectable scaffold system aiding in enhancing stem cell differentiation under normal physiological conditions compared to NFM without LP. The laponite–NFM shows suitability as excellent injectable biomaterials system for stem cell attachment, proliferation and osteogenic differentiation for stem cell transplantation and bone tissue regeneration.     

Clinical Application of Resorbable Polymers in Guided Bone Regeneration

Summary : Guided bone regeneration was shown to be successful in vitro and in vivo using resorbable or nonresorbable materials. Resorbable material has the advantage of progressive substitution by bone. Resorbable polymers of ∝-hydroxy acids like polylactide or polyglycolide are commonly used for tissue engineering and in guided bone regeneration. In clinical studies, guided bone regeneration was successful in non-weight bearing bone, e.g. in dental surgery and craniofacial surgery. This paper reports the preliminary result of using resorbable poly(L/DL-lactide) 80/20% scaffolds in weight bearing bone with infected large segmental defects as well as in small bony defects of hand due to benign tumour, bone graft donor sites and as an adjunct for joint fusion. Resorbable polylactide implants were used in the form of membranes, large 3-D sponges, chips or as injectable paste. Implants were impregnated with marrow blood to add an osteoinductive component. Long-term follow up revealed that these implants are promising candidates for bone graft substitutes.     

Natural lotus root-based scaffolds for bone regeneration

A high incidence of bone defects and the limitation of autologous bone grafting require 3 D scaffolds for bone repair. Compared with synthetic materials, natural edible materials possess outstanding advantages in terms of biocompatibility, bioactivities and low manufacturing cost for bone tissue engineering. In this work, attracted by the natural porous/fabric structure, good biocompatibility and bioactivities of the lotus root, the lotus root-based scaffolds were fabricated and investigated the...     

Synergistic Effects of Beta Tri‐Calcium Phosphate and Porcine‐Derived Decellularized Bone Extracellular Matrix in 3D‐Printed Polycaprolactone Scaffold on Bone Regeneration

Bone‐derived extracellular matrix (ECM) is widely used in studies on bone regeneration because of its ability to provide a microenvironment of native bone tissue. However, a hydrogel, which is a main type of ECM application, is limited to use for bone graft substitutes due to relative lack of mechanical properties. The present study aims to fabricate a scaffold for guiding effective bone regeneration. A polycaprolactone (PCL)/beta‐tricalcium phosphate (β‐TCP)/bone decellularized extracellular matrix (dECM) scaffold capable of providing physical and physiological environment are fabricated using 3D printing technology and decoration method. PCL/β‐TCP/bone dECM scaffolds exhibit excellent cell seeding efficiency, proliferation, and early and late osteogenic differentiation capacity in vitro. In addition, outstanding results of bone regeneration are observed in PCL/β‐TCP/bone dECM scaffold group in the rabbit calvarial defect model in vivo. These results indicate that PCL/β‐TCP/bone dECM scaffolds have an outstanding potential as bone graft substitutes for effective bone regeneration.     

Medical applications of organic-inorganic hybrid materials within the field of silica-based bioceramics

Research on bioceramics has evolved from the use of inert materials for mere substitution of living tissues towards the development of third-generation bioceramics aimed at inducing bone tissue regeneration. Within this context hybrid bioceramics have remarkable features resulting from the synergistic combination of both inorganic and organic components that make them suitable for a wide range of medical applications. Certain bioceramics, such as ordered mesoporous silicas, can exhibit different kind of interaction with organic molecules to develop different functions. The weak interaction of these host matrixes with drug molecules confined in the mesoporous channels allows these hybrid systems to be used as controlled delivery devices. Moreover, mesoporous silicas can be used to fabricate three (3D)-dimensional scaffolds for bone tissue engineering. In this last case, different osteoinductive agents (peptides, hormones and growth factors) can be strongly grafted to the bioceramic matrix to act as attracting signals for bone cells to promote bone regeneration process. Finally, recent research examples of organic-inorganic hybrid bioceramics, such as stimuli-responsive drug delivery systems and nanosystems for targeting of cancer cells and gene transfection, are also tackled in this tutorial review (64 references).     

Biomineralized polymer matrix composites for bone tissue repair: a review

Bone defects caused by trauma, infection or bone tumor resection, are highly prevalent. A small number(5%–10%) of these injuries fail to heal due to non-union and require surgical intervention. Currently, the principal treatment options for these defects are autografts, allografts, xenografts or synthetic grafts. The main problems associated with these therapies include pain,infection and donor site morbidity. Bone tissue engineering is a diverse field that focuses on the regeneration of bone by combining cells, scaffolds, growth factors and dynamic forces. There have been many recent studies utilizing biomineralized polymer matrix composites which mimic the natural structure of bone. The principal focus of this review is on recent advances in the synthesis of various types of biomineralized polymer matrix composite. Examples of the biomineralization of naturallyderived and synthetic polymers widely used for bone engineering are also summarized.     

Silk Fibroin Combined with Electrospinning as a Promising Strategy for Tissue Regeneration

The development of tissue engineering scaffolds is of great significance for the repair and regeneration of damaged tissues and organs. Silk fibroin (SF) is a natural protein polymer with good biocompatibility, biodegradability, excellent physical and mechanical properties and processability, making it an ideal universal tissue engineering scaffold material. Nanofibers prepared by electrospinning have attracted extensive attention in the field of tissue engineering due to their excellent mechanical properties, high specific surface area, and similar morphology as to extracellular matrix (ECM). The combination of silk fibroin and electrospinning is a promising strategy for the preparation of tissue engineering scaffolds. In this review, the research progress of electrospun silk fibroin nanofibers in the regeneration of skin, vascular, bone, neural, tendons, cardiac, periodontal, ocular and other tissues is discussed in detail.     

Poly(1,8-octanediol citrate)/bioactive glass composite with improved mechanical performance and bioactivity for bone regeneration

Poly(1,8-octanediol-co-citrate)(POC) represents a new promising biocompatible and biodegradable polyester that has been extensively investigated for soft tissue engineering. However, the poor mechanical performance and poor bioactivity limit its application in bone regeneration. In this study, a series of POC/bioactive glasses(BG) composites were developed using 45 S5 Bioglass~ and a phytic acidderived bioactive glass(referred as PSC). The results indicated that calcium in BG could enhance the crosslinking of the POC/BG composites by forming calcium dicarboxylate bridges and thus improve their mechanical performances. When PSC were used, the composites exhibited significantly better mechanical properties compared to composites with 45 S5 Bioglass~. For example, by incorporating70 wt% PSC, the compressive strength of POC/PSC composites could be improved to approximately50 MPa and modulus 1.3±0.1 GPa. Furthermore, all these POC/PSC composites showed good in vitro bioactivity and cellular biocompatibility. Histology results in femoral condyle defects of Sprague-Dawley rats indicated that the POC/PSC samples integrated well with surrounding tissues and stimulated bone regeneration. The improved mechanical properties and bioactivity of POC/PSC composites make them promising for potential application in bone regeneration.     

A co-templated approach to hierarchically mesoporous–macroporous bioactive glasses (MMBG) scaffolds for bone tissue regeneration

In this paper, one kind of well-ordered hierarchical mesoporous–macroporous bioactive glasses (MMBG) scaffolds with large pore size of 60–120 μm and mesoporous phase in inner-wall has synthesized successfully. This method used stem core of corn as macroporous template and P123 as mesoporous template. The final samples have replicated the structure of the macroporous plant templates precisely. Since the aperture and pore structure of different plants are variable, it provides a possible way for the synthesis of materials with various aperture holes and pore structure. The organizational structure of final sample is benefit to transport and storage guest molecule, making these hierarchical porous materials have more superior performance and application in the field of macromolecules separation, bone tissue regeneration, and drug delivery, etc. The in vitro tests indicated hierarchical MMBG scaffolds have well capacity for inducing the HA growth. They have the potential to satisfy the demands of bone tissue engineering regeneration.     

Tofu as excellent scaffolds for potential bone regeneration

Biomimetic scaffolds present the promising potential for bone regeneration. As a natural gel-like traditional food, tofu with porous architecture and proved biological safety indicated a good potential to be a natural scaffold and easy to be improved by surface modification. Hereon, we fabricated the tofubased scaffolds and systematically explored the potential for bone tissue engineering. In addition, the collagen has been introduced by simple coating to further enhance the surface compatibility of the tofubased scaffold in bone regeneration. The results showed that the tofu-based scaffolds possessed good porous structure and cytocompatibility. Notably, the tofu-based scaffolds could improve the expression of osteogenesis-related genes and proteins, leading to better bone regeneration after 2 months of implantation. All the results indicated that tofu would become an outstanding sustainable natural porous scaffold for bone regeneration with excellent bioactivities.     

Tofu as excellent scaffolds for potential bone regeneration

Biomimetic scaffolds present the promising potential for bone regeneration. As a natural gel-like traditional food, tofu with porous architecture and proved biological safety indicated a good potential to be a natural scaffold and easy to be improved by surface modification. Hereon, we fabricated the tofu-based scaffolds and systematically explored the potential for bone tissue engineering. In addition, the collagen has been introduced by simple coating to further enhance the surface compatibility of the tofu-based scaffold in bone regeneration. The results showed that the tofu-based scaffolds possessed good porous structure and cytocompatibility. Notably, the tofu-based scaffolds could improve the expression of osteogenesis-related genes and proteins, leading to better bone regeneration after 2 months of implantation. All the results indicated that tofu would become an outstanding sustainable natural porous scaffold for bone regeneration with excellent bioactivities.     

Gelatin/PLLA sponge-like scaffolds allow proliferation and osteogenic differentiation of human mesenchymal stromal cells

Tissue engineering has the potential to supply constructs capable of restoring the normal function of native tissue following injury. Poly(L-lactic acid) (PLLA) scaffolds are amongst the most commonly used biodegradable polymers in tissue engineering and previous studies performed on ovine fibroblasts have showed that addition of gelatin creates a favorable hydrophilic microenvironment for the growth of these cells. The attractiveness of using mesenchymal stromal cells (MSCs) in tissue regeneration is that they are able to differentiate into several lines including osteoblasts. In this study, we investigated the ability of gelatin/PLLA sponges to support the adhesion, proliferation, and osteogenic differentiation of human MSCs isolated from the bone marrow of four donors. [Figure: see text].     

有机-无机杂化骨修复材料

寻找理想的骨修复材料一直是骨科领域的研究热点之一。骨修复材料已由最初单纯取代天然骨组织的惰性材料向具有诱导骨组织再生功能的生物活性材料发展,其中有机-无机杂化材料由于有机和无机组分在分子/纳米水平的复合使其能够最大程度地实现二者的优势互补和协同优化,近年来受到广泛关注。本文着重介绍了有机-无机杂化骨修复材料近些年来的研究进展,并对其发展趋势进行了展望。     

A fast on-demand preparation of injectable self-healing nanocomposite hydrogels for efficient osteoinduction

Injectable hydrogels have been considered as promising materials for bone regeneration,but their osteoinduction and mechanical performance are yet to be improved.In this study,a novel biocompatible injectable and self-healing nano hybrid hydrogel was on-demand prepared via a fast(within 30 s) and easy gelation approach by reversible Schiff base formed between-CH=O of oxidized sodium alginate(OSA) and-NH_2 of glycol chitosan(GCS) mixed with calcium phosphate nanoparticles(CaP NPs).Its raw materials can be ready in large quantities by a simple synthesis process.The mechanical strength,degradation and swelling behavior of the hydrogel can be readily controlled by simply controlling the molar ratio of-CH=O and-NH_2.This hydrogel exhibits pH responsiveness,good degradability and biocompatibility.The hydrogel used as the matrix for mesenchymal stem cells can significantly induce the proliferation,differentiation and osteoinduction in vitro.These results showed this novel hydrogel is an ideal candidate for applications in bone tissue regeneration and drug delivery.     

A 3D Bioprinted Nanoengineered Hydrogel with Photoactivated Drug Delivery for Tumor Apoptosis and Simultaneous Bone Regeneration via Macrophage Immunomodulation

One of the significant challenges in bone tissue engineering (BTE) is the healing of traumatic tissue defects owing to the recruitment of local infection and delayed angiogenesis. Herein, a 3D printable multi-functional hydrogel composing polyphenolic carbon quantum dots (CQDs, 100 µg mL⁻¹) and gelatin methacryloyl (GelMA, 12 wt%) is reported for robust angiogenesis, bone regeneration and anti-tumor therapy. The CQDs are synthesized from a plant-inspired bioactive molecule, 1, 3, 5-trihydroxybenzene. The 3D printed GelMA-CQDs hydrogels display typical shear-thinning behavior with excellent printability. The fabricated hydrogel displayed M2 polarization of macrophage (Raw 264.7) cells via enhancing anti-inflammatory genes (e.g., IL-4 and IL10), and induced angiogenesis and osteogenesis of human bone mesenchymal stem cells (hBMSCs). The bioprinted hBMSCs are able to produce vessel-like structures after 14 d of incubation. Furthermore, the 3D printed hydrogel scaffolds also show remarkable near infra-red (NIR) responsive properties under 808 nm NIR light (1.0 W cm⁻²) irradiation with controlled release of antitumor drugs (≈49%) at pH 6.5, and thereby killing the osteosarcoma cells. Therefore, it is anticipated that the tissue regeneration and healing ability with therapeutic potential of the GelMA-CQDs scaffolds may provide a promising alternative for traumatic tissue regeneration via augmenting angiogenesis and accelerated immunomodulation.     

Trends in development of calcium phosphate-based ceramic and composite materials for medical applications: Transition to nanoscale

Current status and lines of research were considered for calcium phosphate-based ceramic materials intended for application in new technologies for damaged bone tissue regeneration. The main trend is toward mimicking the composition, structure, and properties of biological bone tissues by ceramic materials. This necessitated developmental efforts on synthesizing polysubstituted, in particular nanocrystalline, biphasic calcium phosphates and on preparing ceramics and composite materials thereof. The progress achieved in this area was reviewed, and certain benefits associated with medical application of these materials were discussed.