Regenerative biology: the emerging field of tissue repair and restoration

Regenerative biology has now been recognized as a new field with certain aims and goals. One direction of this new field is to understand the basic mechanisms by which tissues can be repaired and restored. The other direction examines the possibility of using this basic knowledge to apply it to medicine with the goal to clinically repair damaged tissues. Regeneration of tissues can occur by the differentiation of stem cells (local or non-local) or by the transdifferentiation of local terminally differentiated cells. While the transdifferentiation aspects are old, during the past few years many data have accumulated regarding the existence of stem cells and their participation in tissue renewal. This review will present an overview of the potential of all vertebrate organs to regenerate and of the basic mechanisms involved.     

Tissue engineering and regenerative medicine –where do we stand?

Tissue Engineering (TE) in the context of Regenerative Medicine (RM) has been hailed for many years as one of the most important topics in medicine in the twenty-first century. While the first clinically relevant TE efforts were mainly concerned with the generation of bioengineered skin substitutes, subsequently TE applications have been continuously extended to a wide variety of tissues and organs. The advent of either embryonic or mesenchymal adult stem-cell technology has fostered many of the efforts to combine this promising tool with TE approaches and has merged the field into the term Regenerative Medicine. As a typical example in translational medicine, the discovery of a new type of cells called Telocytes that have been described in many organs and have been detected by electron microscopy opens another gate to RM. Besides cell-therapy strategies, the application of gene therapy combined with TE has been investigated to generate tissues and organs. The vascularization of constructs plays a crucial role besides the matrix and cell substitutes. Therefore, novel in vivo models of vascularization have evolved allowing axial vascularization with subsequent transplantation of constructs. This article is intended to give an overview over some of the most recent developments and possible applications in RM through the perspective of TE achievements and cellular research. The synthesis of TE with innovative methods of molecular biology and stem-cell technology appears to be very promising.     

Flow cytometry in radiation research: past, present and future

Flow cytometry is an invaluable technique in research and clinical laboratories. The technique has been applied extensively to many areas of radiation research at both the experimental and clinical level. In the past few years, there has been a significant increase in the capabilities of modern flow cytometers to undertake multicolor analysis in a user-friendly manner. The developments in cytometric technology are being matched by the rapid development of new reagents, new fluorochromes and new platforms such as bead arrays. These developments are facilitating many new applications in both basic and clinical research that have relevance for many fields of biology, including radiation research. This review provides a historical overview of the application of flow cytometry to radiobiology and an update on how technology and reagents have changed and cites examples of new applications relevant to radiation researchers. In addition, some entirely new flow instrumentation is currently under development that has significant potential for applications in radiation research.     

Technology and medicine

Technology, which is older than science, has been of vital importance in the development of modern medicine. Even so, there are voices of dissent to be heard. The disenchantment with technology expressed by Aldous Huxley in Brave new world has been echoed by contemporary writers on the technology of modern medicine. Medicine is seen by some to have been dehumanized by technology, and techniques that are expensive are thought to be consuming a greater proportion of health resources than they deserve. The practice of medicine has, nevertheless, been transformed by modern technology and diagnostic techniques and therapeutic measures undreamed of a few short decades ago are now commonplace. There is no reason why these developments should be any more dehumanizing than the use of similar techniques in modern transportation or communication, nor is their expense out of proportion when compared with other demands on the nation's purse. British workers have been at the forefront of many recent advances. Yet, even though the National Health Service provides a ready market for the products of British medical technology, the nation depends to an inordinate degree on imported products. In the development of appropriate medical technology there is an urgent need for better communication between inventors, scientists, industrialists and the National Health Service. At the same time there is an equal need for improved evaluation of untried techniques. The pressure for a central integrating body to coordinate resources could well be supported by the establishment of evaluation units in the different health authorities in this country.     

Emerging mammalian gene switches for controlling implantable cell therapies

Engineered cell-based therapies have emerged as a new paradigm in modern medicine, with several engineered T cell therapies currently approved to treat blood cancers and many more in clinical development. Tremendous progress in synthetic biology over the past two decades has allowed us to program cells with sophisticated sense-and-response modules that can effectively control therapeutic functions. In this review, we highlight recent advances in mammalian synthetic gene switches, focusing on devices designed for therapeutic applications. Although many gene switches responding to endogenous or exogenous molecular signals have been developed, the focus is shifting towards achieving remote-controlled production of therapeutic effectors by stimulating implanted engineered cells with traceless physical signals, such as light, electrical signals, magnetic fields, heat or ultrasound.     

Peripheral blood mononuclear cell secretome for tissue repair

For almost two decades, cell-based therapies have been tested in modern regenerative medicine to either replace or regenerate human cells, tissues, or organs and restore normal function. Secreted paracrine factors are increasingly accepted to exert beneficial biological effects that promote tissue regeneration. These factors are called the cell secretome and include a variety of proteins, lipids, microRNAs, and extracellular vesicles, such as exosomes and microparticles. The stem cell secretome has most commonly been investigated in pre-clinical settings. However, a growing body of evidence indicates that other cell types, such as peripheral blood mononuclear cells (PBMCs), are capable of releasing significant amounts of biologically active paracrine factors that exert beneficial regenerative effects. The apoptotic PBMC secretome has been successfully used pre-clinically for the treatment of acute myocardial infarction, chronic heart failure, spinal cord injury, stroke, and wound healing. In this review we describe the benefits of choosing PBMCs instead of stem cells in regenerative medicine and characterize the factors released from apoptotic PBMCs. We also discuss pre-clinical studies with apoptotic cell-based therapies and regulatory issues that have to be considered when conducting clinical trials using cell secretome-based products. This should allow the reader to envision PBMC secretome-based therapies as alternatives to all other forms of cell-based therapies.     

Advances in tissue and organ replacement

Applications of regenerative medicine technology may offer new therapies for patients with injuries, end-stage organ failure, or other clinical problems. Currently, patients suffering from diseased and injured organs can be treated with transplanted organs. However, there is a shortage of donor organs that is worsening yearly as the population ages and new cases of organ failure increase. Scientists in the field of regenerative medicine and tissue engineering are now applying the principles of cell transplantation, material science, and bioengineering to construct biological substitutes that will restore and maintain normal function in diseased and injured tissues. The stem cell field is a rapidly advancing aspect of regenerative medicine as well, and new discoveries here create new options for this type of therapy. For example, therapeutic cloning, in which the nucleus from a donor cell is transferred into an enucleated oocyte in order to extract pluripotent embryonic stem cells from the resultant embryo, provides another source of cells for cell-based tissue engineering applications. While stem cells are still in the research phase, some therapies arising from tissue engineering endeavors have already entered the clinical setting, indicating that regenerative medicine holds promise for the future.     

Bioethical aspects of regenerative and reproductive medicine

The birth announced in 1997 of Dolly, the lamb cloned from the somatic mammary cells of an adult ewe, and the discovery of human embryonic stem cells in 1998 have been the most exciting developments in the biological sciences in the past decade. Reproductive somatic cell nuclear transfer (SCNT) in additional species has been inefficient in that relatively few births, harmful side effects and high fetal and neonatal death rates have resulted from many attempts. Ongoing debates about the ethics of reproductive SCNT have revealed that some researchers regard human reproductive SCNT as morally unacceptable in all circumstances, others see merit in reproductive SCNT in certain circumstances and others await more information before making judgment about the ethical status of the procedure. Regenerative medicine and emerging biotechnologies started to revolutionize the practice of medicine. Advances in stem cell biology, including embryonic and postnatal somatic stem cells, have made the prospect of tissue regeneration a potential reality. Mammal cloning experiments have provided new impetus to the prospect of regenerative medicine through stem cell research. The procedure of SCNT could be used to create the raw material to replace defective or senescent tissue as a natural extension of the biology of stem cells. Researchers working in reproductive medicine should consider the potential hope given to many patients against the requisite and ethically contentious creation of human blastocysts for therapeutic intent.     

用《组合中药学》的理论开发新型中药

我们以现代科技理论为出发点,提出了<组合中药学>新理论体系,试图使中外学者对中药的认识趋于一致.中药的本质就是"组合".无论是单方或复方都是一个庞大的分子库.具有相同或相似功能的分子组合成一个群体.这些群体表现出特定的药效."组合"有三层意思生药的组合、活性分子群的组合与特定疗效的组合.分子群是特定药效功能的物质基础.<组合中药学>就是从<组合分子>水平上研究中药及其药效的物质基础,阐明中药活性部位的相互作用与药效的相互关系及其作用机制.<组合中药学>的三个新概念中药功效分子族具有相似药效作用的一类分子的组合,其骨架及功能团相同或相似.单味中药表征性组合分子单味中药药效的代表性功效分子族,即主要药效分子组合.单味中药非表性组合分子单味中药表征性分子以外的其它功效分子族,即辅助药效分子的组合.<组合中药学>的主要研究范围中药药效的组合分子学基础(植物化学,天然产物);组合分子的药理学基础(分子生物学,细胞生物学,药理学).本文提出了应用<组合中药学>研究新型中药的新方法.     

Engineering towards functional tissues and organs

Engineering towards fully functional tissues and organs fall under the widespread banner of tissue engineering and regenerative biology/medicine (which includes therapeutics). This endeavor is said to evolve from the Greek mythical story¹ where Prometheus is punished by Zeus who assigned a long winged eagle to feed on Prometheus’s liver, for stealing fire from the Gods. It is said that Prometheus’s liver grew as much it was eaten. Thus, conceptualizing tissue engineering and regenerative medicine. This in its very early stages was investigated by Alexis Carrel and Charles Lindbergh at the Rockefeller Institute for Medical Research² and was subsequently clinically implemented in 1954 in renal transplantation medicine in the United States by Joseph Murray and colleagues.3 Both Carrel and Murray were awarded Nobel Prizes for their findings and contributions.⁴ Although these are hallmarks for tissue engineering and regenerative medicine, there are many obstacles and to date we are still grappling with some of these hurdles whist others have to a great extent been understood, and could be argued as being to some degree resolved. Some obstacles we face today range from (1) the ability to grow specialized and unspecialized cells outside the human body in practical quantities while retaining their native functionality, (2) biomaterials (advancing the development of synthetic materials for enhanced bioactivity), (3) advanced approaches for forming three-dimensional fully functional tissues and or organs to (4) controlled vascularization, which are a few examples amongst many.     

Brain and Mind

In the last few years great progress has been made in many fields of knowledge. Technology has moved forward with rapid strides, and with the appearance of self-regulating systems it has moved to a new stage. Significant progress has been achieved in physics and biology; new branches of medicine have been formulated and are being developed; and substantial changes have also been noted in a sphere of particular relevance and importance for each of us, in psychology, the science of man's mental life and the laws of his behavior.     

Evolutionary psychiatry: foundations,progress and challenges

Evolutionary biology provides a crucial foundation for medicine and behavioral science that has been missing from psychiatry. Its absence helps to explain slow progress; its advent promises major advances. Instead of offering a new kind of treatment, evolutionary psychiatry provides a scientific foundation useful for all kinds of treatment. It expands the search for causes from mechanistic explanations for disease in some individuals to evolutionary explanations for traits that make all members of a species vulnerable to disease. For instance, capacities for symptoms such as pain, cough, anxiety and low mood are universal because they are useful in certain situations. Failing to recognize the utility of anxiety and low mood is at the root of many problems in psychiatry. Determining if an emotion is normal and if it is useful requires understanding an individual's life situation. Conducting a review of social systems, parallel to the review of systems in the rest of medicine, can help achieve that understanding. Coping with substance abuse is advanced by acknowledging how substances available in modern environments hijack chemically mediated learning mechanisms. Understanding why eating spirals out of control in modern environments is aided by recognizing the motivations for caloric restriction and how it arouses famine protection mechanisms that induce binge eating. Finally, explaining the persistence of alleles that cause serious mental disorders requires evolutionary explanations of why some systems are intrinsically vulnerable to failure. The thrill of finding functions for apparent diseases is evolutionary psychiatry's greatest strength and weakness. Recognizing bad feelings as evolved adaptations corrects psychiatry's pervasive mistake of viewing all symptoms as if they were disease manifestations. However, viewing diseases such as panic disorder, melancholia and schizophrenia as if they are adaptations is an equally serious mistake in evolutionary psychiatry. Progress will come from framing and testing specific hypotheses about why natural selection left us vulnerable to mental disorders. The efforts of many people over many years will be needed before we will know if evolutionary biology can provide a new paradigm for understanding and treating mental disorders.     

Cardiac tissue engineering: regeneration of the wounded heart

New solutions are needed to regenerate hearts damaged by myocardial infarction, to overcome bad prognosis of patients with heart failure, and to address the shortage of heart donors. In the past few years, cardiac tissue engineering has emerged as a new and ambitious approach that combines knowledge from material chemistry with cell biology and medicine. In this short review, we present an overview on the most promising materials and cell-therapy strategies used in the past few years for the regeneration of the wounded heart.     

Developing a Curriculum for Evolutionary Medicine: Case Studies of Scurvy and Female Reproductive Tract Cancers

Most early evolutionary thinkers came from medicine, yet evolution has had a checkered history in medical education. It is only in the last few decades that serious efforts have begun to be made to integrate evolutionary biology into the medical curriculum. However, it is not clear when, where (independently or as part of preclinical or clinical teaching courses) and, most importantly, how should medical students learn the basic principles of evolutionary biology applied to medicine, known today as evolutionary or Darwinian medicine. Most clinicians are ill-prepared to teach evolutionary biology and most evolutionary biologists ill-equipped to formulate clinical examples. Yet, if evolutionary science is to have impact on clinical thought, then teaching material that embeds evolution within the clinical framework must be developed. In this paper, we use two clinical case studies to demonstrate how such may be used to teach evolutionary medicine to medical students in a way that is approachable as well as informative and relevant.     

Hyaluronan.

Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide found in the extracellular matrix, especially of soft connective tissues. It is synthesized in the plasma membrane of fibroblasts and other cells by addition of sugars to the reducing end of the polymer, whereas the nonreducing end protrudes into the pericellular space. The polysaccharide is catabolized locally or carried by lymph to lymph nodes or the general circulation, from where it is cleared by the endothelial cells of the liver sinusoids. The overall turnover rate is surprisingly rapid for a connective tissue matrix component (t1/2 0.5 to a few days). Hyaluronan has been assigned various physiological functions in the intercellular matrix, e.g., in water and plasma protein homeostasis. Hyaluronan production increases in proliferating cells and the polymer may play a role in mitosis. Extensive hyaluronidase-sensitive coats have been identified around mesenchymal cells. They are either anchored firmly in the plasma membrane or bound via hyaluronan-specific binding proteins (receptors). Such receptors have now been identified on many different cells, e.g., the lymphocyte homing receptor CD 44. Interaction between a hyaluronan receptor and extracellular polysaccharide has been connected with locomotion and cell migration. Hyaluronan seems to play an important role during development and differentiation and has other cell regulatory activities. Hyaluronan has also been recognized in clinical medicine. A concentrated solution of hyaluronan (10 mg/ml) has, through its tissue protective and rheological properties, become a device in ophthalmic surgery. Analysis of serum hyaluronan is promising in the diagnosis of liver disease and various inflammatory conditions, e.g., rheumatoid arthritis. Interstitial edema caused by accumulation of hyaluronan may cause dysfunction in various organs.     

Vertebrate limb regeneration and the origin of limb stem cells

The existence of multipotent cells in the adult tissues and organs of those vertebrates that are capable of regeneration has been accepted for decades. Although studies of vertebrate limb regeneration have yet to identify many of the specific molecules involved in regeneration, numerous tissue grafting experiments and studies of cell lineage have contributed significantly to an understanding of the origin, activation, proliferation and cell-cell interactions of these progenitor cells. This has allowed the development of ideas about the regulation of pattern formation to restore the structure and function of lost tissues and organs. An understanding of the molecular mechanisms controlling these processes has lagged behind the dramatic advances achieved with other model organisms. However, given the intense, new research interest in stem cells over the past few years, there is good reason to be encouraged that insights about the biology of mammalian stem cells will accelerate progress in understanding the biology of regeneration in organisms that can regenerate. Advances in regeneration research will then feed back in terms of devising new strategies for therapies to induce regeneration in organisms such as humans that have traditionally been viewed as incapable of regeneration.     

Bio-electrosprays: a novel electrified jetting methodology for the safe handling and deployment of primary living organisms

Electrohydrodynamic jetting (EHDJ) which is also known as electrosprays (ES) has recently been elucidated as a unique electrified biotechnique for the safe handling and deployment of living organisms. This high intensity electric field driven jetting methodology is now referred to as "bioelectrosprays" (BES). Previously these charged jets have only been shown to jet-process immortalized cells which have undergone expected cellular behavior when compared with control cells. In this paper we demonstrate the ability to jet process primary living organisms in the stable conejetting mode. Finally the viability of the bio-electrosprayed living organisms has been assessed employing a flow cytometry approach which forms the discussion in this paper. Our findings further establish BES as a competing biotechnique, which could be employed for the deposition of primary living organisms according to a predetermined active cellular architecture. One day this could be used for the fabrication of viable tissues and organs for repair or replacement. These advanced studies carried out on BES have direct widespread applications ranging from developmental biology to regenerative and therapeutic medicine, which are a few amongst several other areas of study within the life sciences.     

Synergistic photothermal ablative effects of functionalizing carbon nanotubes with a POSS-PCU nanocomposite polymer

ABSTRACT: BACKGROUND: The application of nanotechnology in biology and medicine represents a significant paradigm shift in the approach to the treatment of cancer. Evidence suggests that when exposed to near-infrared radiation (NIR), carbon nanotubes (CNTs) dissipate a substantial amount of heat energy. We have developed a novel nanocomposite polymer, polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU). POSS-PCU displays excellent biocompatibility and has been used in making artificial organs as well as protective coatings for medical devices. RESULTS: Functionalizing (or "coating") CNTs with POSS-PCU confers biocompatibility and increase the amount of heat energy generated, by enhancing dispersion. Here we demonstrate that POSS-PCU-functionalized multi-walled CNTs (MWNTs) act synergistically together when exposed to NIR to thermally ablate cancer cells. CONCLUSION: Given that POSS-PCU has already been used in human in first-in-man studies as trachea, lacrimal duct, bypass graft and other organs, our long-term goal is to take POSS-PCU coated CNTs to clinical studies to address the treatment of cancer by optimizing its therapeutic index and increasing its specificity via antibody conjugation. RESULTS: Functionalizing (or "coating") CNTs with POSS-PCU confers biocompatibility and increase the amount of heat energy generated, by enhancing dispersion. Here we demonstrate that POSS-PCU-functionalized MWNTs act synergistically together when exposed to NIR to thermally ablate cancer cells. CONCLUSION: Given that POSS-PCU has already been used in human in first-in-man studies as trachea, lacrimal duct, bypass graft and other organs, our long-term goal is to take POSS-PCU coated CNTs to clinical studies.     

Targeted alpha and beta radiotherapy: An overview of radiopharmaceutical and clinical aspects

For many years, the role of internal radiotherapy has remained limited to certain historical indications such as thyroid cancers or to academic medical research. However, the recent recognition of theranostics and targeted therapies as one of the cornerstones of the modern concept of personalized medicine, has participated in the promotion of new developments for beta and alpha radiotherapy. In this paper, we will review the emerging radionuclides, radiopharmaceutical developments and advances, as well as the clinical successes that have been made in past few years. The results obtained, for some very promising, could herald in a new era for nuclear medicine. However, as presented in this review, in order to fully exploit its potential, and not to remain static as a promising or emerging therapy, the entire field of nuclear medicine must invest in the implementation of well-designed prospective and comparative studies for targeted radiotherapy.