αvβ3 and α5β1 integrin-specific ligands: From tumor angiogenesis inhibitors to vascularization promoters in regenerative medicine?

Integrins are cell adhesion receptors predominantly important during normal and tumor angiogenesis. A sequence present on several extracellular matrix proteins composed of Arg-Gly-Asp (RGD) has attracted attention due to its role in cell adhesion mediated by integrins. The development of ligands that can bind to integrins involved in tumor angiogenesis and brake disease progression has resulted in new investigational drug entities reaching the clinical trial phase in humans. The use of integrin-specific ligands can be useful for the vascularization of regenerative medicine constructs, which remains a major limitation for translation into clinical practice. In order to enhance vascularization, immobilization of integrin-specific RGD peptidomimetics within constructs is a recommended approach, due to their high specificity and selectivity towards certain desired integrins. This review endeavours to address the potential of peptidomimetic-coated biomaterials as vascular network promoters for regenerative medicine purposes. Clinical studies involving molecules tracking active integrins in cancer angiogenesis and reasons for their failure are also addressed.     

Freeze-gelled silk fibroin protein scaffolds for potential applications in soft tissue engineering

Recently tissue engineering has escalated much interest in biomedical and biotechnological applications. In this regard, exploration of new and suitable biomaterials is needed. Silk fibroin protein is used as one of the most preferable biomaterials for fabrication of scaffolds and several new techniques are being adopted to fabricate silk scaffolds with greater ease, efficiency and perfection. In this study, a freeze gelation technique is used for fabrication of silk fibroin protein 3D scaffolds, which is both time and energy efficient as compared to the conventional freeze drying technique. The fabricated silk fibroin freeze-gelled scaffolds are evaluated micro structurally for morphology with scanning electron microscopy which reveals relatively homogeneous pore structure and good interconnectivity. The pore sizes and porosity of these scaffolds ranges between 60-110 μm and 90-95%, respectively. Mechanical test shows that the compressive strength of the scaffolds is in the range of 20-40 kPa. The applicability to cell culture of the freeze gelled scaffolds has been examined with human keratinocytes HaCat cells which show the good cell viability and proliferation of cells after 5 days of culture suggesting the cytocompatibility. The freeze-gelled 3D scaffolds show comparable results with the conventionally prepared freeze dried 3D scaffolds. Thus, this technique may be used as an alternative method for 3D scaffolds preparation and may also be utilized for tissue engineering applications.     

Carbon nanotubes leading the way forward in new generation 3D tissue engineering

Statistics from the NHS Blood and Transplant Annual Review show that total organ transplants have increased to 4213 in 2012, while the number of people waiting to receive an organ rose to 7613 that same year. Human donors as the origin of transplanted organs no longer meet the ever-increasing demand, and so interest has shifted to synthetic organ genesis as a form of supply. This focus has given rise to new generation tissue and organ engineering, in the hope of one day designing 3D organs in vitro. While research in this field has been conducted for several decades, leading to the first synthetic trachea transplant in 2011, scaffold design for optimising complex tissue growth is still underexplored and underdeveloped. This is mostly the result of the complexity required in scaffolds, as they need to mimic the cells’ native extracellular matrix. This is an intricate nanostructured environment that provides cells with physical and chemical stimuli for optimum cell attachment, proliferation and differentiation. Carbon nanotubes are a popular addition to synthetic scaffolds and have already begun to revolutionise regenerative medicine. Discovered in 1991, these are traditionally used in various areas of engineering and technology; however, due to their excellent mechanical, chemical and electrical properties their potential is now being explored in areas of drug delivery, in vivo biosensor application and tissue engineering. The incorporation of CNTs into polymer scaffolds displays a variety of structural and chemical enhancements, some of which include: increased scaffold strength and flexibility, improved biocompatibility, reduction in cancerous cell division, induction of angiogenesis, reduced thrombosis, and manipulation of gene expression in developing cells. Moreover CNTs’ tensile properties open doors for dynamic scaffold design, while their thermal and electrical properties provide opportunities for the development of neural, bone and cardiac tissue constructs.     

Enabling stem cell therapies for tissue repair: Current and future challenges

Stem cells embody the tremendous potential of the human body to develop, grow, and repair throughout life. Understanding the biologic mechanisms that underlie stem cell-mediated tissue regeneration is key to harnessing this potential. Recent advances in molecular biology, genetic engineering, and material science have broadened our understanding of stem cells and helped bring them closer to widespread clinical application. Specifically, innovative approaches to optimize how stem cells are identified, isolated, grown, and utilized will help translate these advances into effective clinical therapies. Although there is growing interest in stem cells worldwide, this enthusiasm must be tempered by the fact that these treatments remain for the most part clinically unproven. Future challenges include refining the therapeutic manipulation of stem cells, validating these technologies in randomized clinical trials, and regulating the global expansion of regenerative stem cell therapies.     

Prospects for translational regenerative medicine

Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.     

In vivo therapeutic applications of cell spheroids

Spheroids are increasingly being employed to answer a wide range of clinical and biomedical inquiries ranging from pharmacology to disease pathophysiology, with the ultimate goal of using spheroids for tissue engineering and regeneration. When compared to traditional two-dimensional cell culture, spheroids have the advantage of better replicating the 3D extracellular microenvironment and its associated growth factors and signaling cascades. As knowledge about the preparation and maintenance of spheroids has improved, there has been a plethora of translational experiments investigating in vivo implantation of spheroids into various animal models studying tissue regeneration.We review methods for spheroid delivery and how they have been utilized in tissue engineering experiments. We break down efforts in this field by organ systems, discussing applications of spheroids to various animal models of disease processes and their potential clinical implications. These breakthroughs have been made possible by advancements in spheroid formation, in vivo delivery and assessment. There is unexplored potential and room for further research and development in spheroid-based tissue engineering approaches. Regenerative medicine and other clinical applications ensure this exciting area of research remains relevant for patient care.     

神经导管研究与进展

随着机械化程度的提高和交通事业的发展,周围神经损伤发生率大幅度的上升。虽然通过手术的方法可以进行端对端的缝合,但是神经恢复的效果仍然不理想,特别是存在神经短距离缺损时,神经导管可为神经的修复提供一个合适的微环境,使得神经纤维能够再生并顺利到达远端。本文介绍了受损神经恢复效果的评价标准,神经导管材料的研究进展,神经生长因子对神经再生的影响因素及作用机理,和神经导管的制备方法,且在总结前人研究的基础上,给出适合于神经导管支架所需的材料和结构要求。     

半月板组织工程天然支架材料研究进展

当今社会半月板损伤十分常见。近些年,伴随生命科学和生物工程学不断发展,用组织工程原理和技术修复损伤的半月板成为热点。许多支架材料也应运而生并取得良好效果,而天然半月板支架材料起着重要的作用,如何选取理想的天然支架材料已成为这一课题的关键,其材料包含种类繁多,可分为可注射类半月板支架材料,不可注射类半月板材料。每种材料都有其独特的优势及缺陷,根据不同的需要来选择合适的材料。迄今为止,运用组织工程技术还不能完全模拟半月板组织,没有一种材料达到最理想的水平。本文着重介绍半月板组织工程天然支架材料。并对未来半月板组织工程支架材料的研究提出展望。     

Bioreactors for tissue engineering

Bioreactors are essential in tissue engineering, not only because they provide an in vitro environment mimicking in vivo conditions for the growth of tissue substitutes, but also because they enable systematic studies of the responses of living tissues to various mechanical and biochemical cues. The basic principles of bioreactor design are reviewed, the bioreactors commonly used for the tissue engineering of cartilage, bone and cardiovascular systems are assessed in terms of their performance and usefulness. Several novel bioreactor types are also reviewed.     

Stem cell- and scaffold-based tissue engineering approaches to osteochondral regenerative medicine

In osteochondral tissue engineering, cell recruitment, proliferation, differentiation, and patterning are critical for forming biologically and structurally viable constructs for repair of damaged or diseased tissue. However, since constructs prepared ex vivo lack the multitude of cues present in the in vivo microenvironment, cells often need to be supplied with external biological and physical stimuli to coax them toward targeted tissue functions. To determine which stimuli to present to cells, bioengineering strategies can benefit significantly from endogenous examples of skeletogenesis. As an example of developmental skeletogenesis, the developing limb bud serves as an excellent model system in which to study how osteochondral structures form from undifferentiated precursor cells. Alongside skeletal formation during embryogenesis, bone also possesses innate regenerative capacity, displaying remarkable ability to heal after damage. Bone fracture healing shares many features with bone development, driving the hypothesis that the regenerative process generally recapitulates development. Similarities and differences between the two modes of bone formation may offer insight into the special requirements for healing damaged or diseased bone. Thus, endogenous fracture healing, as an example of regenerative skeletogenesis, may also inform bioengineering strategies. In this review, we summarize the key cellular events involving stem and progenitor cells in developmental and regenerative skeletogenesis, and discuss in parallel the corresponding cell- and scaffold-based strategies that tissue engineers employ to recapitulate these events in vitro.     

Nanoscale engineering of extracellular matrix-mimetic bioadhesive surfaces and implants for tissue engineering

Background

The goal of tissue engineering is to restore tissue function using biomimetic scaffolds which direct desired cell fates such as attachment, proliferation and differentiation. Cell behavior in vivo is determined by a complex interaction of cells with extracellular biosignals, many of which exist on a nanoscale. Therefore, recent efforts in tissue engineering biomaterial development have focused on incorporating extracellular matrix- (ECM) derived peptides or proteins into biomaterials in order to mimic natural ECM. Concurrent advances in nanotechnology have also made it possible to manipulate protein and peptide presentation on surfaces on a nanoscale level.

Scope of Review

This review discusses protein and peptide nanopatterning techniques and examples of how nanoscale engineering of bioadhesive materials may enhance outcomes for regenerative medicine.

Major Conclusions

Synergy between ECM-mimetic tissue engineering and nanotechnology fields can be found in three major strategies: (1) Mimicking nanoscale orientation of ECM peptide domains to maintain native bioactivity, (2) Presenting adhesive peptides at unnaturally high densities, and (3) Engineering multivalent ECM-derived peptide constructs.

General Significance

Combining bioadhesion and nanopatterning technologies to allow nanoscale control of adhesive motifs on the cell–material interface may result in exciting advances in tissue engineering.This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine.     

CHITIN — A promising biomaterial for tissue engineering and stem cell technologies

Chitin, after cellulose, is the second most abundant natural polymer. With a 200-year history of scientific research, chitin is beginning to see fruitful application in the fields of stem cell and tissue engineering. To date, however, research in chitin as a biomaterial appears to lag far behind that of its close relative, chitosan, due to the perceived difficulty in processing chitin. This review presents methods to improve the processability of chitin, and goes on further to discuss the unique physicochemical and biological characteristics of chitin that favor it as a biomaterial for regenerative medicine applications. Examples of the latter are presented, with special attention on the qualities of chitin that make it inherently suitable as scaffolds and matrices for tissue engineering, stem cell propagation and differentiation.     

Mathematical modelling of human mesenchymal stem cell proliferation and differentiation inside artificial porous scaffolds

We present a mathematical model for the proliferation and differentiation of human mesenchymal stem cells grown inside artificial porous scaffolds under different oxygen concentrations. The values of parameters in the model are determined by comparison of the model solutions to published experimental data, complemented with a sensitivity analysis of the fitted parameters. It is shown that a simple hypothesis whereby the secretion of extra-cellular matrix (ECM) is oxygen dependent and that ECM itself stimulates cell proliferation is sufficient to explain the experimental data, which under conditions of low oxygen reveals increased total cell proliferation, upregulation of the numbers of undifferentiated cells, and extended lag phase. These results may help further to understand how cells proliferate inside artificial materials and are of importance to the field of tissue engineering.