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Natural polymers for bone repair
Abstract
The incidence of bone disorders and orthopedic surgeries are increasing worldwide representing a premier clinical need. The serious limitation in conventional therapies has led to a new discipline, the so-called bone tissue engineering (BTE), which aims to explore novel functional regeneration strategies via the synergistic combination of biomaterial design with cell and factor therapies. The core of BTE is the design of an “ideal” synthetic bone graft that mimics the tissue from macro- to nanoscale level, including the biochemical and biophysical cues of bone extracellular matrix. The engineering of natural polymers to obtain biomaterials is one of the most attractive options, mainly due to their similarities with the bone extracellular matrix (ECM), chemical versatility and good biological performance. In this chapter, the most relevant natural polymeric formulations for bone repair and the principal stimulus proposed as contributors or mediators for promoting cell activity and bone tissue formation are discussed. Finally, we bring up the current challenges and future directions in bone regeneration focused on the recent advances in 3D printing of customized bone grafts.
... In vivo bone mineralization has inspired the design of advanced biomaterials, socalled biomimetic, mimicking the hierarchical organization and composition of native tissue at nanoscale level [8][9][10][11]. Bone is a nanocomposite made up of self-assembled collagen fibers (accounting for 35 wt.%) strengthened by inter and intrafibrillar mineralization of apatite (Ap) nanocrystals (65 wt.%) [12]. Ap nanoparticles consist on non-stoichiometric hydroxyapatite [HA, Ca10(PO4)6(OH)2] containing foreign ions in its structure, e.g., CO3 2-, Mg 2+ , Sr 2+ [13]. ...
... Herein, bioinspired scaffolds mimicking the osteogenic niche of cancellous bone have been designed through biomimetic mineralization of recombinant collagen and freezedrying. This technique is one of the most common methodologies used to fabricate tridimensional porous scaffolds with tailored pore size, porosity and pore distribution (aligned or isotropic structures) [10,35]. These are critical parameters that directly affect the fluid shear stress sensed by the cells when cell medium is perfused through the scaffold in the bioreactor [36]. ...
In bone tissue engineering, the design of 3D systems capable of recreating composition, architecture and micromechanical environment of the native extracellular matrix (ECM) is still a challenge. While perfusion bioreactors have been proposed as potential tool to apply biomechanical stimuli, its use has been limited to a low number of biomaterials. In this work, we propose the culture of human mesenchymal stem cells (hMSC) in biomimetic mineralized recombinant collagen scaffolds with a perfusion bioreactor to simultaneously provide biochemical and biophysical cues guiding stem cell fate. The scaffolds were fabricated by mineralization of recombinant collagen in the presence of magnesium (RCP.MgAp). The organic matrix was homogeneously mineralized with apatite nanocrystals, similar in composition to those found in bone. X-Ray microtomography images revealed isotropic porous structure with optimum porosity for cell ingrowth. In fact, an optimal cell repopulation through the entire scaffolds was obtained after 1 day of dynamic seeding in the bioreactor. Remarkably, RCP.MgAp scaffolds exhibited higher cell viability and a clear trend of up-regulation of osteogenic genes than control (non-mineralized) scaffolds. Results demonstrate the potential of the combination of biomimetic mineralization of recombinant collagen in presence of magnesium and dynamic culture of hMSC as a promising strategy to closely mimic bone ECM.
... Natural polymers were employed as the first biodegradable biomaterials in medical applications due to their improved biological performance, excellent biodegradability, and high chemical versatility compared to traditional synthetic materials [2,177]. Hyaluronic acid, chitosan, collagen, gelatin, silk, cellulose, and alginate are among the most commonly used natural polymers. ...
Patients suffering bone fractures in different parts of the body require implants that will enable similar function to that of the natural bone that they are replacing. Joint diseases (rheumatoid arthritis and osteoarthritis) also require surgical intervention with implants such as hip and knee joint replacement. Biomaterial implants are utilized to fix fractures or replace parts of the body. For the majority of these implant cases, either metal or polymer biomaterials are chosen in order to have a similar functional capacity to the original bone material. The biomaterials that are employed most often for implants of bone fracture are metals such as stainless steel and titanium, and polymers such as polyethene and polyetheretherketone (PEEK). This review compared metallic and synthetic polymer implant biomaterials that can be employed to secure load-bearing bone fractures due to their ability to withstand the mechanical stresses and strains of the body, with a focus on their classification, properties, and application.
... Also, they possess functional units that attract cells and create a suitable vivo-like microenvironment for tissue remodeling [4]. Additionally, their biocompatibility, biodegradability, and bioactivity are typically better than synthetic polymers [5]. ...
Natural polymers have been used in the biomedical fields for decades, mainly derived from animals and plants with high similarities with biomacromolecules in the human body. As an alkaline polysaccharide, chitosan (CS) attracts much attention in tissue regeneration and drug delivery with favorable biocompatibility, biodegradation, and antibacterial activity. However, to overcome its mechanical properties and degradation behavior drawbacks, a robust fibrous protein-silk fibroin (SF) was introduced to prepare the CS/SF composites. Not only can CS be combined with SF via the amide and hydrogen bond formation, but also their functions are complementary and tunable with the blending ratio. To further improve the performances of CS/SF composites, natural (e.g., hyaluronic acid and collagen) and synthetic biopolymers (e.g., polyvinyl alcohol and hexanone) were incorporated. Also, the CS/SF composites acted as slow-release carriers for inorganic non-metals (e.g., hydroxyapatite and graphene) and metal particles (e.g., silver and magnesium), which could enhance cell functions, facilitate tissue healing, and inhibit bacterial growth. This review presents the state-of-the-art and future perspectives of different biomaterials combined with CS/SF composites as sponges, hydrogels, membranes, particles, and coatings. Emphasis is devoted to the biological potentialities of these hybrid systems, which look rather promising toward a multitude of applications.
... The first biodegradable biomaterials used medically were natural polymers. Contrasted to traditional synthetic materials, natural polymers display excellent chemical versatility, superior biodegradability, and ameliorated biological performance [33]. Among the commonly utilised natural polymers are the following polymers: chitosan, hyaluronic acid, gelatin, collagen, silk, alginate, and cellulose. ...
Every year, many people suffer from bone fractures because of accidents or diseases. Majority of these fractures are too complicated to be treated with conventional medicine and must be mended surgically using non-degradable metal inserts. Such treatment may result in refusal and protection against stress, but may also require another surgical procedure to get rid of the metal inserts. Additionally, biodegradable metals that can readily erode inside the human body come with certain complications. These aspects prompted scientists to find alternatives to metals. Some researchers began to focus on the field of polymers which have shown significant promise in replacing metals. In orthopaedics, degradable polymeric fixation appliances are being studied to substitute metallic implants, eliminating stress protection and avoiding another implant removal surgery. The new generation of bioabsorbable and degradable polymeric implants are free from toxic and mutagenic effects. Nevertheless, these implants have several issues, including mechanical stiffness and strength limitations, unfavourable tissue responses, foreign body reactions, the late response of degraded tissue, and infection due to crystallinity and hydrophobicity. This review discusses the alternative synthetic polymer implant materials available that can be employed and their properties.
... Regardless of the origin, they must be biocompatible to avoid the induction of immune response besides being sterilizable to be safely incorporated into the host tissues, biodegradable to disappear from the tissue after fulfilling their function, and bioactive to stimulate tissue responses ( Fig. 1) [36,37]. Natural polymers (chitosan, gelatin, collagen, cellulose, alginates, etc.) are more preferred than synthetic ones (polylactide-co-glycolide (PLGA), polycaprolactone (PCL), polylactic acid (PLA), fibronectin, polyurethane, etc.) as they have higher biocompatibility, excellent biodegradability, and minimal toxicity [38]. Moreover, plant-derived biomaterials have been explored widely to replace animal-derived ones due to major concerns regarding variability, ethical and environmental issues, also, animal-derived products are of higher cost and need more extraction and purification processes [39]. ...
Tissue engineering has emerged as an interesting field nowadays; it focuses on accelerating the auto-healing mechanism of tissues rather than organ transplantation. It involves implanting an In Vitro cultured initiative tissue or a scaffold loaded with tissue regenerating ingredients at the damaged area. Both techniques are based on the use of biodegradable , biocompatible polymers as scaffolding materials which are either derived from natural (e.g. alginates, celluloses, and zein) or synthetic sources (e.g. PLGA, PCL, and PLA). This review discusses in detail the recent applications of different biomaterials in tissue engineering highlighting the targeted tissues besides the in vitro and in vivo key findings. As well, smart biomaterials (e.g. chitosan) are fascinating candidates in the field as they are capable of elucidating a chemical or physical transformation as response to external stimuli (e.g. temperature, pH, magnetic or electric fields). Recent trends in tissue engineering are summarized in this review highlighting the use of stem cells, 3D printing techniques, and the most recent 4D printing approach which relies on the use of smart biomaterials to produce a dynamic scaffold resembling the natural tissue. Furthermore, the application of advanced tissue engineering techniques provides hope for the researchers to recognize COVID-19/host interaction, also, it presents a promising solution to rejuvenate the destroyed lung tissues.
Graphical abstract
... There are various forms of chitosan-based scaffolds in bone tissue engineering, including films, particles, hydrogels, fibers, and sponges [117]. Chitosan is introduced as a linear polysaccharide and has favorable biocompatibility, bioactivity, and biodegradability features. ...
The musculoskeletal (MS) system consists of bone, cartilage, tendon, ligament, and skeletal muscle, which forms the basic framework of the human body. This system plays a vital role in appropriate body functions, including movement, the protection of internal organs, support, hematopoiesis, and postural stability. Therefore, it is understandable that the damage or loss of MS tissues significantly reduces the quality of life and limits mobility. Tissue engineering and its applications in the healthcare industry have been rapidly growing over the past few decades. Tissue engineering has made significant contributions toward developing new therapeutic strategies for the treatment of MS defects and relevant disease. Among various biomaterials used for tissue engineering, natural polymers offer superior properties that promote optimal cell interaction and desired biological function. Natural polymers have similarity with the native ECM, including enzymatic degradation, bio-resorb and non-toxic degradation products, ability to conjugate with various agents, and high chemical versatility, biocompatibility, and bioactivity that promote optimal cell interaction and desired biological functions. This review summarizes recent advances in applying natural-based scaffolds for musculoskeletal tissue engineering.
... Currently, bone defect caused by pathological changes, aging, accidental injury, cancer and other reasons is one of the biggest problems in the field of biomedical engineering [1,2]. Different types of bone scaffolds including ceramics [3,4], metals [5], polymers [6] and composites [7] are used in bone tissue engineering. Despite the wide variety of scaffold technologies, it remains a challenge to select materials that can mimic the structural integrity and biocompatibility of natural bone. ...
At present, the treatment of bone defect is one of the most concerned problems in biomedical fields. Despite the wide variety of scaffolds, there is a challenge to select materials that can mimic the structural integrity and biocompatibility of natural bone. In our study, Gelatin methacryloyl (GelMA) and sodium alginate (Alg) were used to prepare three-dimensional (3 D) GelMA/Alg hybrid hydrogel, which can simulate the structure and biological function of natural extracellular matrix (ECM) due to their high water content and porous structure. The interconnected and homogeneous pores of the scaffold facilitate the transport of nutrients during the bone regeneration. Then hydroxyapatite (HA) coated GelMA/Alg (GelMA/Alg-HA) hydrogel was obtained by sequential mineralization. The mineralized hydrogel was obtained by immersing hydrogel alternately in a solution of calcium and phosphorus at 37 °C. The hydrogel was modified with a coating of HA under a mild condition. The calcium crosslinked Alg could provide nucleation sites for HA crystals. And the sequential mineralization will improve the physical properties and osteoinductivity of the hydrogels by introducing HA, which is similar to the mineral component of natural bone. Analytical results confirmed that the HA particles were uniformly distributed in the surface of the hydrogels and the mineral contents were about 40% after three cycles. The compressive strength was improved from 22.43 ± 6.39 kPa to 131.03 ± 9.26 kPa. In addition, MC3T3-E1 cell co-culture experiments shown that the mineralized GelMA/Alg-HA hybrid hydrogel possess good biocompatibility, which is conducive to the growth of new bone tissue and bone repair.
... A hybrid scaffold (Hy-scaffold) that mimics the bone composition, was developed by blending Gel/MgHA microparticles with a polymeric matrix consisting of Gel and Chit. The mineral component (Gel/MgHA) was developed through biomineralization, a process that allows the growth of biomimetic MgHA nanocrystals in the gelatin matrix via a neutralization reaction and a simultaneous pH variation, exploiting MgHA and gelatin functional groups aggregation abilities [13,28,29]. The mineralization of MgHA on gelatin produced mineralized flakes that were added to the polymer blend forming a hybrid hydrogel used as base matrix for the scaffold (Hy-scaffold) development (Fig. 1a). ...
Many medical-related scientific discoveries arise from trial-error patterns where the processes involved must be refined and modified continuously before any product could be able to reach the final costumers. One of the elements affecting negatively these processes is the inaccuracy of two-dimension (2D) standard culture systems, carried over in plastic plates or similar, in replicating complex environments and patterns. Consequently, animal tests are required to validate every in vitro finding, at the expenses of more funds and ethical issues. A possible solution relies in the implementation of three-dimension (3D) culture systems as a fitting gear between the 2D tests and in vivo tests, aiming to reduce the negative in vivo outcomes. These 3D structures are depending from the comprehension of the extracellular matrix (ECM) and the ability to replicate it in vitro. In this article a comparison of efficacies between these two culture systems was taken as subject, human mesenchymal stem cells (hMSCs) was utilized and a hybrid scaffold made by a blend of chitosan, gelatin and biomineralized gelatin was used for the 3D culture system.
Many different materials have been utilized by orthopedic surgeons for repairing the bones and polymers are one of them. Polymers have been used as a key component in biomedical applications and their uses are still expanding. However, the requirements of polymers used in bone and orthopedic surgery have been thoroughly investigated. The present chapter presents the various types of polymers used in bone repair, orthopedic surgery, and tissue engineering. The chapter also provides a general discussion about polymers and biodegradable polymers to be used in the above application.
There has been significant interest in the recent past to develop injectable hydrogel scaffolds that follow minimally invasive implantation procedures towards efficient healing and regeneration of defective bone tissues. Such scaffolds offer several advantages, as they can be injected into the irregularly shaped defect and can act as a low‐density aqueous reservoir, incorporating necessary components for bone tissue repair and augmentation. Considering that bone is a biocomposite of natural biopolymer and bioapatite nanofiller, there has been a growing trend to develop nanocomposite scaffolds by combining biopolymers and inorganic nanofillers to biomimic the hierarchical nanostructure and composition of natural bone. Furthermore, the nanocomposite scaffolds can be tailored to have patient‐specific bone properties, which can lead to better biological responses. The present article begins with the introduction, followed by an overview of polymer matrices, property requirements, and crosslinking techniques employed for injectable hydrogels. Various strategies to develop injectable composites, with emphasis on nanocomposite hydrogels incorporating bioinert and bioactive nanofillers have been discussed. The fundamental challenges related to the development of injectable hydrogel nanocomposite scaffolds and the research efforts directed towards solving these problems have also been reviewed. Finally, future trends and conclusions on new generation injectable hydrogel nanocomposite bone scaffolds have been discussed in this article.
Bioactive glasses have found significant space, clinically, in the reconstruction of hard tissue. Several bioactive glass compositions, such as 45S5 or S53P3, are FDA approved and have been used to treat patients with high success. The unicity of bioactive glass lies in their high versatility that enables to load the biomaterial with a large variety of ions of therapeutic interest. Just to cite a few, Mg and Sr have been found to favor the bone formation and production of stronger bone, B and Cu have been tested and demonstrated unique angiogenic properties, and finally Ag or Cu exhibit unique antimicrobial properties. Given the complexity of the bone (structure and properties), researchers have focused lately in developing new composites and hybrids that could even further enhance bone formation while overcoming some of the drawbacks inherent to the glass material. Studies on composites have led to the development of materials that are less brittle while still promoting bioactivity and osteoconduction. Hybrid biomaterials have recently emerged and are promising as they mimic more closely the bone structure and open the path to cellularized graft that can be bioprinted to match the defect size and shape. This chapter aims at giving an overview of the unique properties of bioactive glasses and how the development of composites and hybrids can lead to more efficient graft being proposed to future patients.
Bone defects, with second highest demand for surgeries around the globe, may lead to serious health issues and negatively influence patient lives. The advances in biomedical engineering and sciences have led to the development of several creative solutions for bone defect treatment. This review provides a brief summary of bone graft materials, an organized overview of top-down and bottom-up (bio)manufacturing approaches, plus a critical comparison between advantages and limitations of each method. Additive manufacturing techniques and their operation mechanisms in detail are specifically discussed. Next, the hybrid methods and promising future directions for bone grafting are reviewed while giving a comprehensive United States Food and Drug Administration (US-FDA) regulatory science perspective, biocompatibility concepts and assessments, and clinical considerations to translate a technology from a research laboratory to the market. The topics covered in this review can potentially fuel future research efforts in bone tissue engineering, and perhaps can also provide novel insights for other tissue engineering applications.
Self-assembled peptides and proteins have turned out to be excellent templates for the growth of inorganic minerals trying to emulate natural biomineralization processes. Doing this, researchers have developed complex sophisticate...
Additive manufacturing facilitates the design of porous metal implants with detailed internal architecture. A rationally designed porous structure can provide to biocompatible titanium alloys biomimetic mechanical and biological properties for bone regeneration. However, increased porosity results in decreased material strength. The porosity and pore sizes that are ideal for porous implants are still controversial in the literature, complicating the justification of a design decision. Recently, metallic porous biomaterials have been proposed for load-bearing applications beyond surface coatings. This recent science lacks standards, but the Quality by Design (QbD) system can assist the design process in a systematic way. This study used the QbD system to explore the Quality Target Product Profile and Ideal Quality Attributes of additively manufactured titanium porous scaffolds for bone regeneration with a biomimetic approach. For this purpose, a total of 807 experimental results extracted from 50 different studies were benchmarked against proposed target values based on bone properties, governmental regulations, and scientific research relevant to bone implants. The scaffold properties such as unit cell geometry, pore size, porosity, compressive strength, and fatigue strength were studied. The results of this study may help future research to effectively direct the design process under the QbD system.
Hybrid superparamagnetic microspheres with bone-like composition, previously developed by a bio-inspired assembling/mineralization process, are evaluated for their ability to uptake and deliver recombinant human bone morphogenetic protein-2 (rhBMP-2) in therapeutically-relevant doses along with prolonged release profiles. The comparison with hybrid non-magnetic and with non-mineralized microspheres highlights the role of nanocrystalline, nanosize mineral phases when they exhibit surface charged groups enabling the chemical linking with the growth factor and thus moderating the release kinetics. All the microspheres show excellent osteogenic ability with human mesenchymal stem cells whereas the hybrid mineralized ones show a slow and sustained release of rhBMP-2 along 14 days of soaking into cell culture medium with substantially bioactive effect, as reported by assay with C2C12 BRE-Luc cell line. It is also shown that the release extent can be modulated by the application of pulsed electromagnetic field, thus showing the potential of remote controlling the bioactivity of the new micro-devices which is promising for future application of hybrid biomimetic microspheres in precisely designed and personalized therapies.
A new concept of biomaterials for antibiotic‐free therapy of bacterial vaginosis (BV) is here proposed. These biomaterials are obtained by entrapping two probiotic biofilms, viz., Lactobacillus fermentum (Lf ) and Lactobacillus acidophilus (La ) into scaffolds of self‐assembled collagen fibers (col). An in‐depth characterization and viability assays are performed on the resulting biomaterials. Results demonstrated that the collagen matrix plays a multifold role in improving the probiotic efficacy in a BV‐simulated environment: i) it acts as a host to the formation of the probiotic biofilm, ii) it protects live probiotics during storage under harsh conditions, iii) it enhances the metabolic activity of entrapped probiotics thereby restoring the pH of BV‐simulated microenvironment, and iv) it enhances the adhesion of probiotics to the simulated vaginal mucosa. These collective properties make these biomaterials as promising candidates for treating BV without antibiotics. In addition, the approach here presented can be adapted for the treatment of other complex microbial infections.
Even though degradation and damage to bone and cartilage tissue can be resolved naturally, but there is a great challenge to regenerate functional tissue due to multiple pathological conditions. To treat the diseased/ damaged bone and cartilage tissue as well as to improve or maintain its natural functions and structure, there are different strategies being developed for repair and regeneration of these tissues. Various innovative researches lead to remarkable improvement in clinical outcome of defective bone and cartilage treatments. Biomaterial based scaffolds which are capable of supporting cell growth and applied for replacement of tissue in vivo for both bone and cartilage. The review also delineates about the tissue engineering bioreactors for the recreation of frameworks to recellularise the graft in vitro by presenting them to physiologically significant mechanical or potentially hydrodynamic stimulation condition. This review summarizes and discusses the strategies for regeneration and repair of bone and cartilage tissue, current scenario and application.
Bone regeneration is a coordinated process mainly regulated by multiple growth factors. Vascular endothelial growth factor (VEGF) stimulates angiogenesis and bone morphogenetic proteins (BMPs) induce osteogenesis during bone healing process. The aim of this study was to investigate how these growth factors released locally and sustainably from nano-cellulose (NC) simultaneously effect bone formation. A biphasic calcium phosphate (BCP)-NC-BMP2-VEGF (BNBV) scaffold was fabricated for this purpose. The sponge BCP scaffold was prepared by replica method and then loaded with 0.5% NC containing BMP2-VEGF. Growth factors were released from NC in a sustainable manner from 1 to 30 days. BNBV scaffolds showed higher cell attachment and proliferation behavior than the other scaffolds loaded with single growth factors. Bare BCP scaffolds and BNBV scaffolds seeded with rat bone marrow mesenchymal stem cells were implanted ectopically and orthotopically in nude mice for 4 weeks. No typical bone formation was exhibited in BNBV scaffolds in ectopic sites. BMP2 and VEGF showed positive effects on new bone formation in BNBV scaffolds, with and without seeded stem cells, in the orthotopic defects. This study demonstrated that the BNBV scaffold could be beneficial for improved bone regeneration. Stem cell incorporation into this scaffold could further enhance the bone healing process.
3D printing, an additive manufacturing based technology for precise 3D construction, is currently widely employed to enhance applicability and function of cell laden scaffolds. Research on novel compatible biomaterials for bioprinting exhibiting fast crosslinking properties is an essential prerequisite toward advancing 3D printing applications in tissue engineering. Printability to improve fabrication process and cell encapsulation are two of the main factors to be considered in development of 3D bioprinting. Other important factors include but are not limited to printing fidelity, stability, crosslinking time, biocompatibility, cell encapsulation and proliferation, shear-thinning properties, and mechanical properties such as mechanical strength and elasticity. In this review, we recite recent promising advances in bioink development as well as bioprinting methods. Also, an effort has been made to include studies with diverse types of crosslinking methods such as photo, chemical and ultraviolet (UV). We also propose the challenges and future outlook of 3D bioprinting application in medical sciences and discuss the high performance bioinks.
In the cell-printing process, bioink has been considered as an extremely important component for successful fabrication of macroscale cell-laden structures. Bioink should be non-toxic, biocompatible, and printable. To date, alginate has been widely used as a whole or partial component of bioink because it is non-toxic to embedded cells and even it can provide good printability with rapid gelation under calcium ions. However, alginate bioinks do not possess cell-activating ability. To overcome the shortcomings of alginate-based bioinks, a new collagen bioink, which was mixed with human adipose stem cells (hASCs) and crosslinked with a polyphenol (tannic acid), was proposed. The feasibility of the bioink was demonstrated using several in vitro assessments for comparison of the macroscale porous cell-laden collagen/polyphenol structure containing the hASCs with the conventional alginate-based cell-laden structure. The levels of the metabolic activity, including the cell viability and cell proliferation, of the cell-laden collagen structure were significantly higher than those of the control (alginate-based cell-laden structure). The results show that the newly designed bioink and cell-laden structure are potentially new outstanding components for regeneration of various tissues.
Cell-laden scaffolds are widely investigated in tissue engineering because they can provide homogenous cell distribution after long culture periods, and deposit multiple types of cells into a designed region. However, producing a bioceramic 3D cell-laden scaffold is difficult because of the low processability of cell-loaded bioceramics. Therefore, designing a 3D bioceramic cell-laden scaffold is important for ceramic-based tissue regeneration. Here, we propose a new strategy to fabricate an alpha-tricalcium-phosphate (α-TCP)/collagen cell-laden scaffold, using preosteoblasts (MC3T3-E1), in which the volume fraction of the ceramic exceeded 70% and was fabricated using a two-step printing process. To fabricate a multi-layered cell-laden scaffold, we manipulated processing parameters, such as the diameter of the printing nozzle, pneumatic pressure, and volume fraction of α-TCP, to attain a stable processing region. A cell-laden pure collagen scaffold and an α-TCP/collagen scaffold loaded with cells via a simple dipping method were used as controls. Their pore geometry was similar to that of the experimental scaffold. Physical properties and bioactivities showed that the designed scaffold demonstrated significantly higher cellular activities, including metabolic activity and mineralization, compared with those of the controls. Our results indicate that the proposed cell-laden ceramic scaffold can potentially be used for bone regeneration.
Background:
Spinal fusion is a common procedure used for surgical treatment of spinal deformity. In recent years, many bone graft substitutes (BGS) have been developed to provide good arthrodesis when the available autologous bone harvested from the patient is not enough. The aim of this study was to analyze the use of a new-generation composite material (RegenOss) made of Mg-hydroxyapatite nanoparticles nucleated on type I collagen to obtain long posterolateral fusion in adult scoliosis surgery.
Methods:
A total of 41 patients who underwent spinal fusion for the treatment of adult scoliosis were retrospectively analyzed. According to Lenke classification, visual analog scale (VAS) score and Oswestry Disability Index (ODI) score, radiographic rates of bone union were evaluated before surgery and at 6, 12 and 36 months of follow-up. Fusion was considered to be successful when criteria for Lenke grade A or B were satisfied. Patient-related risk factors were considered for the evaluation of the final outcome.
Results:
At 36-month follow-up, radiographic evidence of spinal fusion was present in the majority of patients (95.1%). A time-dependent statistically significant improvement was evidenced after surgery for all clinical outcomes evaluated. Based on the demographic data collected, there were no statistically significant factors determining fusion. The correction of deformity was maintained at different time points. No intraoperative or postoperative complications were recorded.
Conclusions:
The present study demonstrated that RegenOss can safely be used to achieve good arthrodesis when associated with autologous bone graft to obtain long spinal fusion in the treatment of adult scoliosis.
Tissue engineering has become a promising strategy for repairing damaged cartilage and bone tissue. Among the scaffolds for tissue-engineering applications, injectable hydrogels have demonstrated great potential for use as three-dimensional cell culture scaffolds in cartilage and bone tissue engineering, owing to their high water content, similarity to the natural extracellular matrix (ECM), porous framework for cell transplantation and proliferation, minimal invasive properties, and ability to match irregular defects. In this review, we describe the selection of appropriate biomaterials and fabrication methods to prepare novel injectable hydrogels for cartilage and bone tissue engineering. In addition, the biology of cartilage and the bony ECM is also summarized. Finally, future perspectives for injectable hydrogels in cartilage and bone tissue engineering are discussed.
There is a pressing need for long-term, controlled drug release for sustained treatment of chronic or persistent medical conditions and diseases. Guided drug delivery is difficult because therapeutic compounds need to survive numerous transport barriers and binding targets throughout the body. Nanoscale protein-based polymers are increasingly used for drug and vaccine delivery to cross these biological barriers and through blood circulation to their molecular site of action. Protein-based polymers compared to synthetic polymers have the advantages of good biocompatibility, biodegradability, environmental sustainability, cost effectiveness and availability. This review addresses the sources of protein-based polymers, compares the similarity and differences, and highlights characteristic properties and functionality of these protein materials for sustained and controlled drug release. Targeted drug delivery using highly functional multicomponent protein composites to guide active drugs to the site of interest will also be discussed. A systematical elucidation of drug-delivery efficiency in the case of molecular weight, particle size, shape, morphology, and porosity of materials will then be demonstrated to achieve increased drug absorption. Finally, several important biomedical applications of protein-based materials with drug-delivery function—including bone healing, antibiotic release, wound healing, and corneal regeneration, as well as diabetes, neuroinflammation and cancer treatments—are summarized at the end of this review.
Biomineralized scaffolds are an attractive option for bone tissue engineering, being similar to native bone. However, optimization is difficult, due to complex interplay between architecture, chemistry and mechanics. Utilizing biomimetic nucleation, linear mineralized scaffolds were created from a collagen type I based recombinant peptide (RCP). Osteoblast mineralization was assessed, in response to changes in scaffold architecture, hydroxyapatite (HA) content and mechanics. Changes in scaffold pore size (150 - 450 μm) had little effect on mRNA levels, but influenced cell proliferation, achieving a balance between nutrient diffusion and surface area for cell attachment at 300 μm. Increasing the scaffold mechanical strength, from 2.9-5.2 kPa, enhanced the expression of osteocalcin, a late marker of mineralization. Further addition of HA, up to 20wt%, increased osteoblast mineralization, without altering the compressive modulus. Thus, it was shown that architectural cues influence cellular proliferation while the scaffold chemistry and mechanics independently contribute to gene expression.
The objective of this study is to evaluate the cellviability and hemocompatibility of starch-based hydrogelsfor maxillofacial bone regeneration. Seven starch-basedhydrogels were prepared: three loaded with 0.5, 1 and 2%calcium carbonate (Sigma Aldrich, St. Louis, MO, USA);three loaded with 2, 3 and 4% hydroxyapatite (SigmaAldrich); and one not loaded as a control. A 10 M NaOHwas then added to induce hydrogel formation. Humanosteoblasts were cultured on each hydrogel for 72 h. AnMTS assay (Cell Titer96; PROMEGA, Madison, WI, USA)was used to assess cell viability. Hemocompatibility testingwas conducted with normal human blood in the followingconditions: 100 mg of each hydrogel in contact with900 lL of whole blood for 15 min at 37 C under lateralstirring. Higher percentages of cell viability were observedin starch-based hydrogels loaded with hydroxyapatite ascompared with the control. The hemolysis test showed ahemolysis level lower than 2%. Acti vated partial throm-boplastin time and prothrombin time were unchanged,while platelet counting showed a slight decrease whencompared with controls.
Hydrogels are hydrophilic, three-dimensional networks that are able to absorb large quantities of water or biological fluids, and thus have the potential to be used as prime candidates for biosensors, drug delivery vectors, and carriers or matrices for cells in tissue engineering. In this critical review article, advantages of the hydrogels that overcome the limitations from other types of biomaterials will be discussed. Hydrogels, depending on their chemical composition, are responsive to various stimuli including heating, pH, light, and chemicals. Two swelling mechanisms will be discussed to give a detailed understanding of how the structure parameters affect swelling properties, followed by the gelation mechanism and mesh size calculation. Hydrogels prepared from natural materials such as polysaccharides and polypeptides, along with different types of synthetic hydrogels from the recent reported literature, will be discussed in detail. Finally, attention will be given to biomedical applications of different kinds of hydrogels including cell culture, self-healing, and drug delivery.
A variety of engineered scaffolds have been created for tissue engineering using polymers, ceramics and their composites. Biomimicry has been adopted for majority of the three-dimensional (3D) scaffold design both in terms of physicochemical properties, as well as bioactivity for superior tissue regeneration. Scaffolds fabricated via salt leaching, particle sintering, hydrogels and lithography have been successful in promoting cell growth in vitro and tissue regeneration in vivo. Scaffold systems derived from decellularization of whole organs or tissues has been popular due to their assured biocompatibility and bioactivity. Traditional scaffold fabrication techniques often failed to create intricate structures with greater resolution, not reproducible and involved multiple steps. The 3D printing technology overcome several limitations of the traditional techniques and made it easier to adopt several thermoplastics and hydrogels to create micro-nanostructured scaffolds and devices for tissue engineering and drug delivery. This review highlights scaffold fabrication methodologies with a focus on optimizing scaffold performance through the matrix pores, bioactivity and degradation rate to enable tissue regeneration. Review highlights few examples of bioactive scaffold mediated nerve, muscle, tendon/ligament and bone regeneration. Regardless of the efforts required for optimization, a shift in 3D scaffold uses from the laboratory into everyday life is expected in the near future as some of the methods discussed in this review become more streamlined.
Statement of significance:
Collagen and apatite are the main constituents regulating the mechanical properties of bone. Hence, an improved understanding of the impact of mineralization on these properties is of large interest for the scientific community. This paper presents systematic studies of synthetic collagen microfibers with increasing apatite content and their response to tensile stress by using a novel self-made electromechanical device combined with a Raman spectrometer for molecular level studies. The impact of apatite on the mechanical and molecular response of collagen is evaluated giving important insights into the interaction between the mineral and organic phases. Therefore our findings expand the fundamental understanding of the mechanics of the apatite/collagen system relevant for the design of bio-composites with similar bio-mimicking properties for e.g. bone regrowth in medical applications.
The basic building block of the extra-cellular matrix in native tissue is collagen. As a structural protein, collagen has an inherent biocompatibility making it an ideal material for regenerative medicine. Cellular response, mediated by integrins, is dictated by the structure and chemistry of the collagen fibers. Fiber formation, via fibrillogenesis, can be controlled in vitro by several factors: pH, ionic strength, and collagen structure. After formation, fibers are stabilized via cross-linking. The final bioactivity of collagen scaffolds is a result of both processes. By considering each step of fabrication, scaffolds can be tailored for the specific needs of each tissue, improving their therapeutic potential.
Silk proteins are natural biopolymers that have extensive structural possibilities for chemical and mechanical modifications to facilitate novel properties, functions, and applications in the biomedical field. The versatile processability of silk fibroins (SF) into different forms such as gels, films, foams, membranes, scaffolds, and nanofibers makes it appealing in a variety of applications that require mechanically superior, biocompatible, biodegradable, and functionalizable biomaterials. There is no doubt that nature is the world's best biological engineer, with simple, exquisite but powerful designs that have inspired novel technologies. By understanding the surface interaction of silk materials with living cells, unique characteristics can be implemented through structural modifications, such as controllable wettability, high-strength adhesiveness, and reflectivity properties, suggesting its potential suitability for surgical, optical, and other biomedical applications. All of the interesting features of SF, such as tunable biodegradation, anti-bacterial properties, and mechanical properties combined with potential self-healing modifications, make it ideal for future tissue engineering applications. In this review, we first demonstrate the current understanding of the structures and mechanical properties of SF and the various functionalizations of SF matrices through chemical and physical manipulations. Then the diverse applications of SF architectures and scaffolds for different regenerative medicine will be discussed in detail, including their current applications in bone, eye, nerve, skin, tendon, ligament, and cartilage regeneration.
An ideal scaffold should has a good porosity, acceptable mechanical strength, and biocompatible. One of the way to achieved these criteria is to incorporate polymers in the scaffold fabrication. Starch is one of the most common natural polymers that have been used to fabricate tissue engineering scaffold. Previously, starch as a biomedical material has found wider application such as hydrogel and drug delivery system. Hence, by blending starch with other materials such as Hydroxyapatite (HA) might improve scaffold's properties. This paper reviews how the incorporation of starch is significant to the improvement of scaffold fabrication.
Basic calcium phosphate (BCP) crystals have been associated with many diseases due to their activation of signaling pathways that lead to their mineralization and deposition in intra-articular and periarticular locations in the bones. In this study, hydroxyapatite (HAp) has been placed in a polysaccharide network as a strategy to minimize this deposition. This research consisted of the evaluation of varying proportions of the polysaccharide network, cellulose nanocrystals (CNCs), and HAp synthesized via a simple sol-gel method. The resulting biocompatible composites were extensively characterized by means of thermogravimetric analysis (TGA), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), zeta potential, and scanning electron microscopy (SEM). It was found that an nHAp = CNC ratio presented greater homogeneity in the size and distribution of the nanoparticles without compromising the crystalline structure. Also, incorporation of bone morphogenetic protein 2 (BMP-2) was performed to evaluate the effects that this interaction would have in the constructs. Finally, the osteoblast cell (hFOB 1.19) viability assay was executed and it showed that all of the materials promoted greater cell proliferation while the nHAp > CNC proportion with the inclusion of the BMP-2 protein was the best composite for the purpose of this study.
Three-dimensional (3D) bioprinting combines biomaterials, cells and functional components into complex living tissues. Herein, we assembled function-control modules into cell-laden scaffolds using 3D bioprinting. A customized 3D printer was able to tune the microstructure of printed bone mesenchymal stem cell (BMSC)-laden methacrylamide gelatin scaffolds at the micrometer scale. For example, the pore size was adjusted to 282 ± 32 μm and 363 ± 60 μm. To match the requirements of the printing nozzle, collagen microfibers with a length of 22 ± 13 μm were prepared with a high-speed crusher. Collagen microfibers bound bone morphogenetic protein 2 (BMP2) with a collagen binding domain (CBD) as differentiation-control module, from which BMP2 was able to be controllably released. The differentiation behaviors of BMSCs in the printed scaffolds were compared in three microenvironments: samples without CBD-BMP2-collagen microfibers in the growth medium, samples without microfibers in the osteogenic medium and samples with microfibers in the growth medium. The results indicated that BMSCs showed high cell viability (>90%) during printing; CBD-BMP2-collagen microfibers induced BMSC differentiation into osteocytes within 14 days more efficiently than the osteogenic medium. Our studies suggest that these function-control modules are attractive biomaterials and have potential applications in 3D bioprinting.
Polymeric biomaterials have a significant impact in today’s health care technology. Polymer hydrogels were the first experimentally designed biomaterials for human use. In this article the design, synthesis and properties of hydrogels, derived from synthetic and natural polymers, and their use as biomaterials in tissue engineering are reviewed. The stimuli-responsive hydrogels with controlled degradability and
examples of suitable methods for designing such biomaterials, using multidisciplinary approaches from traditional polymer chemistry, materials engineering to molecular biology, have been discussed. Examples of the fabrication of polymer-based biomaterials, utilized for various cell type manipulations for tissue re-generation are also elaborated. Since a highly porous three-dimensional scaffold is crucially important in the cellular process, for tissue engineering, recent advances in the effective methods of scaffold fabrication are described. Additionally, the incorporation of factor molecules for the enhancement of tissue formation and their controlled release is also elucidated in this article. Finally, the future challenges in the efficient fabrication of effective polymeric biomaterials for tissue regeneration and medical device applications are discussed.
Medical advances have led to a welcome increase in life expectancy. However, accompanying longevity introduces new challenges: increases in age-related diseases and associated reductions in quality of life. The loss of skeletal tissue that can accompany trauma, injury, disease or advancing years can result in significant morbidity and significant socio-economic cost and emphasise the need for new, more reliable skeletal regeneration strategies. To address the unmet need for bone augmentation, tissue engineering and regenerative medicine have come to the fore in recent years with new approaches for de novo skeletal tissue formation. Typically, these approaches seek to harness stem cells, innovative scaffolds and biological factors that promise enhanced and more reliable bone formation strategies to improve the quality of life for many. This review provides an overview of recent developments in bone tissue engineering focusing on skeletal stem cells, vascular development, bone formation and the translation from preclinical in vivo models to clinical delivery.
Fish gelatin is an important alternative gelatin which can be considered as Halal free and acceptable by all religions. It is made from fish by-products of which fish skin is the most widely used part. The collogan and gelatin-like property of fish bones and scales coupled with their readily availability make it a potential source for development into gelatin products. This review discusses the potentials for the development and utilization of fish bones and scales in the production of gelatins. It also looks at the raw materials, processes, properties and the improvement of fish gelatins for future commercial use.
Silk/polyethylene glycol (PEG) hydrogels are studied as self-standing bioinks for 3D printing for tissue engineering. The two components of the bioink, silk fibroin protein (silk) and PEG, are both Food and Drug Administration approved materials in drug and medical device products. Mixing PEG with silk induces silk β-sheet structure formation and thus gelation and water insolubility due to physical crosslinking. A variety of constructs with high resolution, high shape fidelity, and homogeneous gel matrices are printed. When human bone marrow mesenchymal stem cells are premixed with the silk solution prior to printing and the constructs are cultured in this medium, the cell-loaded constructs maintain their shape over at least 12 weeks. Interestingly, the cells grow faster in the higher silk concentration (10%, w/v) gel than in lower ones (7.5 and 5%, w/v), likely due to the difference in material stiffness and the amount of residual PEG remaining in the gel related to material hydrophobicity. Subcutaneous implantation of 7.5% (w/v) bioink gels with and without printed fibroblast cells in mice reveals that the cells survive and proliferate in the gel matrix for at least 6 week postimplantation. The results suggest that these silk/PEG bioink gels may provide suitable scaffold environments for cell printing and function.
Bone morphogenetic protein-2 (BMP-2) is a powerful osteoinductive protein; however, there is a need for the development of a safe and efficient BMP-2 release system for bone regeneration therapies. Recombinant extracellular matrix proteins are promising next generation biomaterials since the proteins are well-defined, reproducible and can be tailored for specific applications. In this study, we have developed a novel and versatile BMP-2 delivery system using microspheres from a recombinant protein based on human collagen I (RCP). In general, a two-phase release pattern was observed while the majority of BMP-2 was retained in the microspheres for at least two weeks. Among different parameters studied, the crosslinking and the size of the RCP microspheres changed the in vitro BMP-2 release kinetics significantly. Increasing the chemical crosslinking (hexamethylene diisocyanide) degree decreased the amount of initial burst release (24 h) from 23% to 17%. Crosslinking by dehydrothermal treatment further decreased the burst release to 11%. Interestingly, the 50 and 72 μm-sized spheres showed a significant decrease in the burst release compared to 207-μm sized spheres. Very importantly, using a reporter cell line, the released BMP-2 was shown to be bioactive. SPR data showed that N-terminal sequence of BMP-2 was important for the binding and retention of BMP-2 and suggested the presence of a specific binding epitope on RCP (KD: 1.2 nM). This study demonstrated that the presented RCP microspheres are promising versatile BMP-2 delivery vehicles.
Statement of significance:
The state-of-art of silk biomaterials in bone tissue engineering, covering their wide applications as cell scaffolding matrices to micro-nano carriers for delivering bone growth factors and therapeutic molecules to diseased or damaged site to facilitate bone regeneration, is emphasized here. The review rationalizes that the choice of silk protein as a biomaterial is not only because of its natural polymeric nature, mechanical robustness, flexibility, and wide range of cell compatibility but also because of its ability to template the growth of hydroxyapatite, the chief inorganic component of bone mineral matrix, resulting in improved osteointegration. The discussion extends to the role of inorganic ions such as Si and Ca as a matrix components in combination with silk to influence bone regrowth. The effect of ions or growth factor-loaded vehicle incorporation into regenerative matrix nanotopography is also included.
Bioprinting of three-dimensional constructs mimicking natural-like extracellular matrix has revolutionized biomedical technology. Bioprinting technology circumvents various discrepancies associated with current tissue engineering strategies by providing an automated and advanced platform to fabricate various biomaterials through precise deposition of cells and polymers in a premeditated fashion. However, few obstacles associated with development of 3D scaffolds including varied properties of polymers used and viability, controlled distribution, and vascularization, etc. of cells hinder bioprinting of complex structures. Therefore, extensive efforts have been made to explore the potential of various natural polymers (e.g. cellulose, gelatin, alginate, and chitosan, etc.) and synthetic polymers in bioprinting by tuning their printability and cross-linking features, mechanical and thermal properties, biocompatibility, and biodegradability, etc. This review describes the potential of these polymers to support adhesion and proliferation of viable cells to bioprint cell laden constructs, bone, cartilage, skin, and neural tissues, and blood vessels, etc. for various applications in tissue engineering and regenerative medicines. Further, it describes various challenges associated with current bioprinting technology and suggests possible solutions. Although at early stage of development, the potential benefits of bioprinting technology are quite clear and expected to open new gateways in biomedical, pharmaceutics and several other fields in near future.
Starch as a biopolymer directly extracted from nature has received much attention in recent years due to its strong advantages such as low cost, wide availability, renewability, and total compostability without toxic residues. Starch-based materials always display properties that are less satisfactory than those of traditional polymer materials, which can be ascribed to the inherent characteristics of starch. To make such materials to be truly competitive and to widen its applications, the development of starch-based nano-biocomposites could be a promising solution. This chapter provides the fundamental knowledge related to starch-based nano-biocomposites as well as the most recent developments in this area. Various types of nanofillers that have been used with plasticized starch are discussed such as montmorillonite, cellulose nanowhiskers, and starch nanoparticles. The preparation strategies for starch-based nano-biocomposites with these types of nanofillers and the corresponding dispersion state and related properties are also largely discussed.
Bioprinting as an enabling technology for tissue engineering possesses the promises to fabricate highly mimicked tissue or organs with digital control. As one of the biofabrication approaches, bioprinting has the advantages of high throughput and precise control of both scaffold and cells. Therefore, this technology is not only ideal for translational medicine but also for basic research applications. Bioprinting has already been widely applied to construct functional tissues such as vasculature, muscle, cartilage, and bone. In this review, the authors introduce the most popular techniques currently applied in bioprinting, as well as the various bioprinting processes. In addition, the composition of bioink including scaffolds and cells are described. Furthermore, the most current applications in organ and tissue bioprinting are introduced. The authors also discuss the challenges we are currently facing and the great potential of bioprinting. This technology has the capacity not only in complex tissue structure fabrication based on the converted medical images, but also as an efficient tool for drug discovery and preclinical testing. One of the most promising future advances of bioprinting is to develop a standard medical device with the capacity of treating patients directly on the repairing site, which requires the development of automation and robotic technology, as well as our further understanding of biomaterials and stem cell biology to integrate various printing mechanisms for multi-phasic tissue engineering.
The need of synthetic bone grafts that recreate from macro to nanoscale level the biochemical and biophysical cues of bone extracellular matrix (ECM) has been a major driving force for the development of new generation of biomaterials. In this study, synthetic bone substitutes have been synthesized via biomimetic mineralization of a recombinant collagen type I derived peptide (RCP), enriched in tri-amino acid sequence arginine-glycine-aspartate (RGD). 3D isotropic porous scaffolds of three different compositions are developed by freeze-drying: non-mineralized (RCP, as a control), mineralized (Ap/RCP) and mineralized scaffolds in presence of magnesium (MgAp/RCP) that closely imitate bone composition. The effect of mineral phase on scaffold pore size, porosity and permeability as well as on their in vitro kinetic degradation is evaluated. The ultimate goal is to investigate how chemical (i.e., surface chemistry and ion release from scaffold) together with physical signals (i.e., surface nano-topography) conferred via biomimetic mineralization can persuade and guide Mesenchymal Stem Cells (MSCs) interaction and fate. The three scaffold compositions showed optimum pore size and porosity for osteoconduction, without significant differences between them. The degradation tests confirmed that MgAp/RCP scaffolds presented higher reactivity under physiological condition compared to Ap/RCP ones. The in vitro study revealed an enhanced cell growth and proliferation on MgAp/RCP scaffolds at day 7, 14 and 21. Furthermore, MgAp/RCP scaffolds potentially promoted cell migration through the inner areas reaching the bottom of the scaffold after 14 days. MSCs cultured on MgAp/RCP scaffolds displayed higher gene and protein expressions of osteogenic markers when comparing them with the results of those MSCs grown on RCP or Ap/RCP scaffolds. This work highlights that mineralization of recombinant collagen mimicking bone mineral composition and morphology is a versatile approach to design smart scaffold interface in a 3D model guiding MSC fate. .
This review is intended to give a state of the art description of scaffold-based strategies utilized in Bone Tissue Engineering.
Numerous scaffolds have been tested in the orthopedic field with the aim of improving cell viability, attachment, proliferation and homing, osteogenic differentiation, vascularization, host integration and load bearing. The main traits that characterize a scaffold suitable for bone regeneration concerning its biological requirements, structural features, composition, and types of fabrication are described in detail.
Attention is then focused on conventional and Rapid Prototyping scaffold manufacturing techniques. Conventional manufacturing approaches are subtractive methods where parts of the material are removed from an initial block to achieve the desired shape. Rapid Prototyping techniques, introduced to overcome standard techniques limitations, are additive fabrication processes that manufacture the final three-dimensional object via deposition of overlying layers. An important improvement is the possibility to create custom-made products by means of computer assisted technologies, starting from patient's medical images.
As a conclusion, it is highlighted that, despite its encouraging results, the clinical approach of Bone Tissue Engineering has not taken place on a large scale yet, due to the need of more in depth studies, its high manufacturing costs and the difficulty to obtain regulatory approval.
PUBMED search terms utilized to write this review were: “Bone Tissue Engineering”, “regenerative medicine”, “bioactive scaffolds”, “biomimetic scaffolds”, “3D printing”, “3D bioprinting”, “vascularization” and “dentistry”.
3D bioprinting is a booming method to obtain scaffolds of different materials with predesigned and customized morphologies and geometries. In this review we focus on the experimental strategies and recent achievements in bioprinting major structural proteins (collagen, silk, fibrin), as a particularly interesting technology to reconstruct the biochemical, biophysical composition and hierarchical morphology of natural scaffolds. The flexibility in molecular design offered by structural proteins, combined with the flexibility in mixing, deposition and mechanical processing inherent to bioprinting technologies enables the fabrication of highly functional scaffolds and tissue mimics with a degree of complexity and organization which has just been started to be explored. Here we describe the printing parameters and physical (mechanical) properties of bioinks based on structural proteins, including the biological function of the printed scaffolds. We describe applied printing techniques and cross-linking methods, highlighting the modification implemented to improve scaffold properties. The used cell types, cell viability, and possible construct applications are also reported. We envision that the application of printing technologies to structural proteins will enable unprecedented control over their supramolecular organization, conferring printed scaffolds biological properties and functions close to natural ones.
A bio-inspired mineralisation process was investigated and applied to develop novel hybrid magnetic materials by heterogeneous nucleation of Fe2+/Fe3+-doped hydroxyapatite nanocrystals onto a biopolymeric matrix made of a Type I collagen-based recombinant peptide (RCP). The effect of the synthesis temperature on the phase composition, crystallinity and magnetic properties of the nucleated inorganic phase was studied. The as-obtained magnetic materials were then engineered, by using a water-in-oil emulsification process, into hybrid magnetic microspheres, which were stabilized by de-hydrothermal treatment yielding cross-linking of the macromolecular matrix.
Thorough investigation of the physicochemical, morphological and biological properties of the new hybrid microspheres, as induced by the presence of the inorganic nanophase and controlled iron substitution into hydroxyapatite lattice, revealed bone-like composition, good cytocompatibility, designed shape and size, and tailored magnetization. Such features are interesting and promising for application as new biomaterials with ability of remote activation and control by using external magnetic fields, for smart and personalized applications in medicine, particularly in bone tissue regeneration.
Statement of significance:
Additive manufacturing techniques have given tissue engineers the ability to precisely recapitulate the native architecture present within tissue. In addition, these techniques can be leveraged to create scaffolds with both physical and chemical gradients. This work offers insight into several techniques that can be used to generate graded scaffolds, depending on the desired gradient. Furthermore, it outlines methods to determine if the designed gradient was achieved. This review will help to condense the abundance of information that has been published on the creation and characterization of gradient scaffolds and to provide a single review discussing both methods for manufacturing gradient scaffolds and evaluating the establishment of a gradient.
Natural and synthetic polymeric materials have been widely used in bone tissue engineering due to their similarity with extracellular matrices and considerable biocompatibility and biodegradability. A variety of techniques has been applied to modify the physicochemical, structural, and biological properties of polymeric materials to meet the specific requirements of bone regeneration. This review aims to provide a brief overview of recent progress on the synthesis and fabrication of polymeric materials for bone tissue engineering. Commonly used and innovative processing techniques to fabricate different structural polymer scaffolds and bioactive surface modification of polymer scaffolds to promote bone regeneration are introduced. The mechanical stimulation and immunomodulatory effect of polymeric materials to cells are also discussed.
The basic building block of the extra-cellular matrix in native tissue is collagen. As a structural protein, collagen has an inherent biocompatibility making it an ideal material for regenerative medicine. Cellular response, mediated by integrins, is dictated by the structure and chemistry of the collagen fibers. Fiber formation, via fibrillogenesis, can be controlled in vitro by several factors: pH, ionic strength, and collagen structure. After formation, fibers are stabilized via cross-linking. The final bioactivity of collagen scaffolds is a result of both processes. By considering each step of fabrication, scaffolds can be tailored for the specific needs of each tissue, improving their therapeutic potential.
Tissue engineering is one of the fields of action of regenerative medicine and usually employs a triad of interconnected strategies, namely: the employment of biomaterials to provide suitable physical and chemical environments; the use of cells to establish communication between living tissues and scaffold materials; and the appliance of bioactive agents such as growth factors to stimulate local and/or implanted cell responses. The main objective is to assist the regeneration of tissues damaged by disease or trauma and, in some cases, creating new tissues to replace failing or malfunctioning tissues or organs. Starch can be processed through several techniques to form 3D porous scaffolds, microparticles, and bone cements for a wide range of applications in the biomedical field. Using different synthetic components of starch-based blends tailored by different processing methods and/or incorporation of reinforcement materials/additives, one can achieve distinct structural forms and/or properties.
This study offers new bioactive composite scaffolds from carboxylated starch-chitosan for bone regeneration. In order to introduce COOH groups into the scaffolds, chitosan was first dissolved in citric acid and then mixed with different amounts of starch. Various characterization techniques were used to analyze the structure, morphology, compressive strength, and apatite mineralization of the composites, which were compared to pure chitosan scaffolds. The results indicated that chitosan scaffolds showed the highest pore size and porosity, while no apatite deposition was observed even after 14 days of soaking in simulated body fluid. For composite samples, the pore size and porosity decreased as the starch content increased. In spite of such decrease, the pore size measurements were in the optimal range for bone regeneration. The bone-like apatite mineralization, compressive strength, carboxyl content, and swelling ratio of the composites increased with additional starch. Cell culture experiments demonstrated that higher starch content can enhance proliferation, ALP activity, and mineralization of osteoblast-like cells (MG63).
Collagen: Structure and Mechanics provides a cohesive introduction to collagen-rich tissues, such as tendon, bone, cornea or arterials walls. Written in a clear and didactic manner, this volume reviews current knowledge on hierarchical structure, mechanical properties, deformation and strengthening mechanisms, and discusses many applications in biomaterials and tissue engineering. Researchers in the fields of materials, (bio-)engineering, physics, chemistry and biology will gain an understanding of the structure and mechanical behavior of type I collagen and collagen-based tissues in vertebrates, across all length scales from the molecular (nano) to the organ (macro) level. Collagen: Structure and Mechanics is a reference for new researchers entering this area and can serve also as a basis for lecturing in the interdisciplinary field of biological materials science. © 2008 Springer Science+Business Media, LLC. All rights reserved.
The clinical demand for scaffolds and the diversity of available polymers provide freedom in the fabrication of scaffolds to achieve successful progress in bone tissue engineering (BTE). Chitosan (CS) has drawn much of the attention in recent years for its use as graft material either as alone or in a combination with other materials in BTE. The scaffolds should possess a number of properties like porosity, biocompatibility, water retention, protein adsorption, mechanical strength, biomineralization and biodegradability suited for BTE applications. In this review, CS and its properties, and the role of CS along with other polymeric and ceramic materials as scaffolds for bone tissue repair applications are highlighted.
Bio-inspired synthesis of smart biomaterials is an emerging nano-technological approach to develop new solutions for an ever-raising number of patients affected by degenerative and disabling pathologies. Particularly for purpose of tissue regeneration, the new materials should function as scaffolds with high mimicry of host tissues, in order to instruct cells to perform their task. Due to the complexity of living tissues and limitations of the current fabrication methods, synthesis methods reproducing the biologic processes may exploit the huge information inherent in macromolecular matrices, to build complex nano-composites with regenerative ability. As an example the assembling/mineralization phenomena involved in hard tissues can be mimicked to achieve smart devices able to regenerate different tissues such as joints and periodontium. Besides, the implementation of this approach with remote activation by low magnetic fields of bio-resorbable superparamagnetic apatite nano-phases, may provide new devices enabling activation on demand suitable for non-invasive and more effective therapies.
The rising incidence of bone disorders has resulted in the need for more effective therapies to meet this demand, exacerbated by an increasing ageing population. Bone tissue engineering is seen as a means of developing alternatives to conventional bone grafts for repairing or reconstructing bone defects by combining biomaterials, cells and signalling factors. However, skeletal tissue engineering has not yet achieved full translation into clinical practice as a consequence of several challenges. The use of additive manufacturing techniques for bone biofabrication is seen as a potential solution, with its inherent capability for reproducibility, accuracy and customisation of scaffolds as well as cell and signalling factor delivery. This review highlights the current research in bone biofabrication, the necessary factors for successful bone biofabrication, in addition to the current limitations affecting biofabrication, some of which are a consequence of the limitations of the additive manufacturing technology itself.
https://www.oulu.fi/spareparts/ebook_topics_in_t_e_vol4/
Collagen-based biomedical materials have developed into important, clinically effective materials used in a range of devices that have gained wide acceptance. These devices come with collagen in various formats, including those based on stabilized natural tissues, those that are based on extracted and purified collagens, and designed composite, biosynthetic materials. Further knowledge on the structure and function of collagens has led to on-going developments and improvements. Among these developments has been the production of recombinant collagen materials that are well defined and are disease free. Most recently, a group of bacterial, non-animal collagens has emerged that may provide an excellent, novel source of collagen for use in biomaterials and other applications. These newer collagens are discussed in detail. They can be modified to direct their function, and they can be fabricated into various formats, including films and sponges, while solutions can also be adapted for use in surface coating technologies. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2015.
In recent years, stereolithographic fabrication has advanced greatly in the quality, resolution, and accuracy of manufactured parts. The concurrent development of photocurable resins that are biocompatible, biodegradable, and bioactive has enabled a vast array of biomedical and translation medical applications of stereolithography-based fabrication technologies. Stereolithographic techniques have been readily integrated with medical imaging technologies in order to improve disease diagnosis, preoperative planning, quality and morphology of prosthetics and implants, and functional success of complex surgeries. Furthermore, stereolithography has established itself as one of the primary enabling tools that will be useful for regenerative medicine applications in the coming years. As a whole, the versatility in design, scale, resolution, and broad applicability of stereolithographic technologies render them the ideal enabling technology for biomedical and translational medical applications.
The musculoskeletal system, which includes bone, cartilage, tendon/ligament, and skeletal muscle, is becoming the targets for tissue engineering because of the high need for their repair and regeneration. Numerous factors would affect the use of musculoskeletal tissue engineering for tissue regeneration ranging from cells used for scaffold seeding to the manufacture and structures of materials. The essential function of the scaffolds is to convey growth factors as well as cells to the target site to aid the regeneration of the injury. Among the variety of biomaterials used in scaffold engineering, silk fibroin is recognized as an ideal material for its impressive cytocompatibility, slow biodegradability, and excellent mechanical properties. The current review describes the advances made in the fabrication of silk fibroin scaffolds with different forms such as films, particles, electrospun fibers, hydrogels, three-dimensional porous scaffolds, and their applications in the regeneration of musculoskeletal tissues.
Several synthetic scaffolds are being developed using polymers, ceramics and their composites to overcome the limitations of auto- and allografts. Polymer-ceramic composites appear to be the most promising bone graft substitute since the natural bone itself is a composite of collagen and hydroxyapatite. Ceramics provide strength and osteoconductivity to the scaffold while polymers impart flexibility and resorbability. Natural polymers have an edge over synthetic polymers because of their biocompatibility and biological recognition property. But, very few natural polymer-ceramic composites are available as commercial products, and those few are predominantly based on type I collagen. Disadvantages of using collagen include allergic reactions and pathogen transmission. The commercial products also lack sufficient mechanical properties. This review summarizes the recent developments of biocomposite materials as bone scaffolds to overcome these drawbacks. Their characteristics, in vitro and in vivo performance are discussed with emphasis on their mechanical properties and ways to improve their performance.
There is a growing demand for three-dimensional scaffolds for expanding applications in regenerative medicine, tissue engineering, and cell culture techniques. The material requirements for such three-dimensional structures are as diverse as the applications themselves. A wide range of materials have been investigated in the recent decades in order to tackle these requirements and to stimulate the anticipated biological response. Among the most promising class of materials are inorganic/organic hydrogel composites for regenerative medicine. The generation of synergetic effects by hydrogel composite systems enables the design of materials with superior properties including biological performance, stiffness, and degradation behavior in vitro and in vivo. Here, we review the most important organic and inorganic materials used to fabricate hydrogel composites. We highlight the advantages of combining different materials with respect to their use for biofabrication and cell encapsulation as well as their application as injectable materials for tissue enhancement and regeneration. [GRAPHICS] .