State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective

Scaffold-based bone tissue engineering aims to repair/regenerate bone defects. Such a treatment concept involves seeding autologous osteogenic cells throughout a biodegradable scaffold to create a scaffold-cell hybrid that may be called a tissue-engineered construct (TEC). A variety of materials and scaffolding fabrication techniques for bone tissue engineering have been investigated over the past two decades. This review aims to discuss the advances in bone engineering from a scaffold material point of view. In the first part the reader is introduced to the basic principles of bone engineering. The important properties of the biomaterials and the scaffold design in the making of tissue engineered bone constructs are discussed in detail, with special emphasis placed on the new material developments, namely composites made of synthetic polymers and calcium phosphates. Advantages and limitations of these materials are analysed along with various architectural parameters of scaffolds important for bone tissue engineering, e.g. porosity, pore size, interconnectivity and pore-wall microstructures.     

A dual-application poly (dl-lactic-co-glycolic) acid (PLGA)-chitosan composite scaffold for potential use in bone tissue engineering

The development of patient-friendly alternatives to bone-graft procedures is the driving force for new frontiers in bone tissue engineering. Poly (dl-lactic-co-glycolic acid) (PLGA) and chitosan are well-studied and easy-to-process polymers from which scaffolds can be fabricated. In this study, a novel dual-application scaffold system was formulated from porous PLGA and protein-loaded PLGA/chitosan microspheres. Physicochemical and in vitro protein release attributes were established. The therapeutic relevance, cytocompatibility with primary human mesenchymal stem cells (hMSCs) and osteogenic properties were tested. There was a significant reduction in burst release from the composite PLGA/chitosan microspheres compared with PLGA alone. Scaffolds sintered from porous microspheres at 37 °C were significantly stronger than the PLGA control, with compressive strengths of 0.846 ± 0.272 MPa and 0.406 ± 0.265 MPa, respectively (p < 0.05). The formulation also sintered at 37 °C following injection through a needle, demonstrating its injectable potential. The scaffolds demonstrated cytocompatibility, with increased cell numbers observed over an 8-day study period. Von Kossa and immunostaining of the hMSC-scaffolds confirmed their osteogenic potential with the ability to sinter at 37 °C in situ.     

Variants of self-assembling peptide,KLD-12 that show both rapid fracture healing and antimicrobial properties

KLD-12 (KLD) is a 12-residue self-assembling peptide that can adopt nano-structures and is known for its tissue-engineering properties. Our objective was to introduce antimicrobial attribute to KLD which would help in preventing secondary infection associated with external application of such tissue engineering materials. Considering the net charge of KLD-12, varying number of cationic arginine residues were added to its N-terminus. KLD variants showed appreciable bactericidal properties without any significant increase in cytotoxicity against tested mammalian cells. Further, these variants adopted β-sheet structures and self-assembled into nano-structures comparable to that of KLD. Interestingly, the KLD variants with two (KLD-2R) and three (KLD-3R) arginine residues added to its N-terminus showed significant osteogenic effect which was comparable or better than the original peptide as evident from the alkaline phosphatase activity assay, mineralized nodule formation and expression of different osteogenic genes. Particularly, application of KLD-2R in rats to the site of a drill-hole (0.8 mm diameter) that was created in the femur metaphysis displayed significantly higher bone regeneration compared to that of KLD. The results demonstrate a simple way to improve biological property of a self-assembling peptide with tissue engineering property.     

Regenerative medicine: Current therapies and future directions

Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.     

Advanced hydrogels for treatment of diabetes

Diabetes mellitus is a chronic disease characterized by high levels of glucose in the blood, which leads to metabolic disorders with severe consequences. Today, there is no cure for diabetes. The current management for diabetes and derived medical conditions, such as hyperglycemia, cardiovascular diseases, or diabetic foot ulcer, includes life style changes and hypoglycemia‐based therapy, which do not fully restore euglycemia or the functionality of damaged tissues in patients. This encourages scientists to work outside their boundaries to develop routes that can potentially tackle such metabolic disorders. In this regard, acellular and cellular approaches have represented an alternative for diabetics, although such treatments still face shortcomings related to limited effectiveness and immunogenicity. The advent of biomaterials has brought significant improvements for such approaches, and three‐dimensional extracellular matrix analogs, such as hydrogels, have played a key role in this regard. Advanced hydrogels are being developed to monitor high blood glucose levels and release insulin, as well as serve as a therapeutic technology. Herein, the state of the art in advanced hydrogels for improving treatment of diabetes, from laboratory technology to commercial products approved by drug safety regulatory authorities, will be concisely summarized and discussed.     

Cytomodulin‐functionalized porous PLGA particulate scaffolds respond better to cell migration,actin production and wound healing in rodent model

In the present study, porous PLGA microparticulate scaffolds (PMS_P), surface‐hydrolysed scaffolds (PMS_Hyd) and cytomodulin‐coupled scaffolds (PMS_CM) were prepared and characterized. After coupling the particles with cytomodulin, the size was reduced from 334 µm (span 0.53) to 278 µm due to hydrolysis, and contact angle also decreased from 70.87 ± 8.56 to 31.43 ± 7.43, indicating an increase in hydrophilicity. Surface roughness and pore density increased, along with an increase in surface area from 9.59 ± 0.36 to 16.82 ± 0.064 m²/g after attaching the biomolecule CM onto the PLGA particles. In vitro cell culture experiments on human dermal fibroblasts (HDFs) were performed for 21 days, in which MTT assay indicated two‐fold higher cell proliferation on PMS_Hyd than on PMS_CM; however, cell distribution, cell spreading and actin production were significantly higher on PMS_CM than on other scaffolds. Migration of cells from PMS_CM to a 2D plate was gradual but the migrated cells attained early confluence, indicating the preservation of normal cellular functions. In a full‐thickness wound mouse model, PMS_CM exhibited 80% wound closure within 2 weeks. Further, at the end of week 3, the inflammatory cell count in the PMS_CM group was reduced to one‐third of the control group, while in PMS_P and PMS_Hyd the extent of inflammation was much higher and more severe. In the case of PMS_CM, abundant fibroblast proliferation, early formation of the scar tissue, eschar formation and inward movement of the wound margins (a zipper‐like movement) towards the deeper layers of the skin suggested advanced wound healing. Cytomodulin‐coupled scaffolds ensured better cell spreading and migration and thus enabled rapid wound healing (see Supporting information, Figure S1). Copyright © 2012 John Wiley & Sons, Ltd.     

Development of functional biomaterials with micro‐ and nanoscale technologies for tissue engineering and drug delivery applications

Micro‐ and nanotechnologies have emerged as potentially effective fabrication tools for addressing the challenges faced in tissue engineering and drug delivery. The ability to control and manipulate polymeric biomaterials at the micron and nanometre scale with these fabrication techniques has allowed for the creation of controlled cellular environments, engineering of functional tissues and development of better drug delivery systems. In tissue engineering, micro‐ and nanotechnologies have enabled the recapitulation of the micro‐ and nanoscale detail of the cell's environment through controlling the surface chemistry and topography of materials, generating 3D cellular scaffolds and regulating cell–cell interactions. Furthermore, these technologies have led to advances in high‐throughput screening (HTS), enabling rapid and efficient discovery of a library of materials and screening of drugs that induce cell‐specific responses. In drug delivery, controlling the size and geometry of drug carriers with micro‐ and nanotechnologies have allowed for the modulation of parametres such as bioavailability, pharmacodynamics and cell‐specific targeting. In this review, we introduce recent developments in micro‐ and nanoscale engineering of polymeric biomaterials, with an emphasis on lithographic techniques, and present an overview of their applications in tissue engineering, HTS and drug delivery. Copyright © 2012 John Wiley & Sons, Ltd.     

Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: a combined gene therapy-cell transplantation approach

One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials.     

Vitamin E: A Review of Its Application and Methods of Detection When Combined with Implant Biomaterials

Vitamin E is a common compound used for tocopherols and tocotrienols (α, β, γ, δ); it is the component of many natural products of both plant and animal origin. Thanks to its powerful antioxidant capacity, vitamin E has been very successful in hip and knee arthroplasty, used to confer resistance to oxidation to irradiated UHMWPE. The positive results of these studies have made vitamin E an important object of research in the biomedical field, highlighting other important properties, such as anti-bacterial, -inflammatory, and -cancer activities. In fact, there is an extensive literature dealing with vitamin E in different kinds of material processing, drug delivery, and development of surface coatings. Vitamin E is widely discussed in the literature, and it is possible to find many reviews that discuss the biological role of vitamin E and its applications in food packaging and cosmetics. However, to date, there is not a review that discusses the biomedical applications of vitamin E and that points to the methods used to detect it within a solid. This review specifically aims to compile research about new biomedical applications of vitamin E carried out in the last 20 years, with the intention of providing an overview of the methodologies used to combine it with implantable biomaterials, as well as to detect and characterize it within these materials.