Biologically inspired approaches to drug delivery for nerve regeneration

As the biological processes governing nerve regeneration have become elucidated over the past decades, interest has developed in manipulating these processes to improve nerve regeneration. Drug delivery to the regenerating nerve has the potential for major clinical applications in neurodegenerative diseases, spinal cord injury and peripheral nerve injury or sacrifice. This article reviews the evolution of the field of drug delivery to the regenerating nerve, from simple local applications of neurotrophic agents in solution and osmotic pump delivery, to the existing approaches involving novel biomaterials and genetically manipulated cell populations. A discussion of the various known nerve growth-promoting agents, and the chemical considerations involved in their delivery, is included. A perspective on the role of tissue engineering approaches for nerve regeneration in the future is offered.     

Myocardial repair: from salvage to tissue reconstruction

Cardiac tissue reconstruction following myocardial infarction represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate or replace damaged myocardium. Thus, different novel treatments have been introduced aimed at myocardial salvage and repair. Here, we present a review of recent advancements in cardiac cell, gene-based and tissue engineering therapies. Selected strategies in cell therapy and new tools for myocardial gene transfer are summarized. Finally, we consider novel approaches to myocardial tissue engineering as a platform for the integration of various modalities in an attempt to rejuvenate infarcted tissue in vivo.     

Epigenetic approaches to regeneration of bone and cartilage from stem cells

Introduction: Embryonic stem cells (ESCs) or adult stem cells, especially mesenchymal stem cells (MSCs), have been intensively studied for skeletal tissue regeneration including bone and cartilage. Epigenetic mechanisms play essential roles in stem cell maintenance and differentiation. However, little is known about the epigenetic regulation of osteogenesis and chondrogenesis of stem cells.

Areas covered: In this review, features of ESCs and adult stem cells, epigenetics and chromatin structure, as well as epigenetic mechanisms, such as chromatin remodeling, DNA methylation and histone modifications, polycomb group (PcG) proteins and microRNAs are described. Epigenetic researches of stem cell are introduced.

Expert opinion: Epigenetic alterations of stem cell during the in vitro differentiation can be controlled for clinical applications. MSCs are effective resources for skeletal tissue regeneration in both undifferentiated and differentiated states. Understanding epigenetic signatures of MSC is crucial to maintain the stemness. In addition, investigation of epigenetic changes in the differentiation of MSCs is very important to develop methods or chemicals to promote efficient differentiation of MSCs. Inhibition of PcG protein enhancer of zeste (Ezh2) a chromatin modifier, could be a promising candidate to improve MSC differentiation by decreasing Ezh2-mediated H3K27me3.     

Individual differences in response to phantom limb movement therapy

Purpose.?Phantom limb pain (PLP) is a distressing condition experienced by many amputees. The purpose of this study was to investigate whether motor imagery could be used to treat PLP.

Method.?Four single case studies were conducted. The participants kept a pain diary in which they recorded the intensity of their PLP during a baseline period, general motor imagery training, phantom limb movement therapy and a follow-up period. Qualitative and quantitative (i.e. interrupted time series) analyses were employed to determine whether phantom limb movement therapy had a significant effect on PLP intensity.

Results.?Phantom limb movement therapy significantly reduced intensity of PLP in one participant. One participant gained occasional relief by doing phantom limb movement therapy exercises but did not experience an overall reduction in PLP intensity. The third participant did not experience any relief and the fourth participant reported experiencing the re-emergence of an old pain.

Conclusion.?The results display individual differences in response to phantom limb movement therapy. Individual differences are discussed in the context of motor imagery ability and the phantom limb phenomenon as a multi-dimensional disorder.     

Residual limb osteomyelitis: A case series from a national prosthetic centre

Purpose. To examine the impact of residual limb osteomyelitis (RLO) on the rehabilitation of lower limb amputees.

Method. Retrospective review of the casenotes of patients with RLO. Information sought included details of amputation, clinical features of investigations for and management of RLO and its effect on rehabilitation.

Results. There were seven transfemoral and three transtibial amputees. Indications for amputation were vascular disease in nine cases, trauma in one. In each case, delayed wound healing or residual limb pain prompted radiological, hematological and microbiological investigations. Average time between amputation and diagnosis was 187 days. One patient died before treatment commenced. Two transtibial amputees were treated with intravenous antibiotics while rehabilitating using pylons. The remaining seven transfemoral amputees required surgical intervention and intravenous antibiotics. Five achieved independent ambulation following modification to or replacement of the originally cast prosthesis, averaging 408 days between amputation and commencement of rehabilitation. Two patients have not engaged in rehabilitation.

Conclusion. RLO delays rehabilitation and has significant financial implications, incurred by prolonged hospitalisation, radiological investigations and prosthetic modifications. RLO should be considered in any case of delayed wound healing or residual limb pain in amputees, as earlier diagnosis may reduce the time to commencement of rehabilitation and subsequent independent ambulation.     

Stem cells for tendon tissue engineering and regeneration

Importance of the field: Tendon injuries are common especially in sports activities, but tendon is a unique connective tissue with poor self-repair capability. With advances in stem cell biology, tissue engineering is becoming increasingly powerful for tissue regeneration. Stem cells with capacity of multipotency and self-renewal are an ideal cell source for tissue engineering.

Areas covered in this review: This review focus on discussing the potential strategies including inductive growth factors, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct tendon-lineage differentiation of stem cells for complete tendon regeneration. Attempting to use embryonic stem cells as seed cells for tendon tissue engineering have achieved encouraging results. The combination of chemical and physical signals in stem cell microenvironment could be regulated to induce differentiation of the embryonic stem cells into tendon.

What the reader will gain: We summarize fundamental questions, as well as future directions in tendon biology and tissue engineering.

Take home message: Multifaceted technologies are increasingly required to control stem cell differentiation, to develop novel stem cell-based therapy, and, ultimately, to achieve more effective repair or regeneration of injured tendons.     

Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering

Low back pain is one of the major health problems in industrialized countries, as a leading source of disability in the working population. Intervertebral disc degeneration has been identified as its main cause, being a progressive process mainly characterized by alteration of extracellular matrix composition and water content. Many factors are involved in the degenerative cascade, such as anabolism/catabolism imbalance, reduction of nutrition supply and progressive cell loss. Currently available treatments are symptomatic, and surgical procedures consisting of disc removal are often necessary. Recent advances in our understanding of intervertebral disc biology led to an increased interest in the development of novel biological treatments aimed at disc regeneration. Growth factors, gene therapy, stem cell transplantation and biomaterials‐based tissue engineering might support intervertebral disc regeneration by overcoming the limitation of the self‐renewal mechanism. The aim of this paper is to overview the literature discussing the current status of our knowledge from the degenerative cascade of the intervertebral disc to the latest molecular, cell‐based therapies and tissue‐engineering strategies for disc regeneration. Copyright © 2013 John Wiley & Sons, Ltd.     

Myocardial regeneration in heart failure: integrated development of biological therapeutic approaches

Heart failure currently constitutes one of the greatest health problems in the Western world. Its incidence, far from diminishing or even remaining stable, is actually still increasing in association with the aging of the population and its lifestyle. A better knowledge of physiopathological mechanisms has allowed for the development of new therapeutic focal points and lines of research. Nevertheless, its treatment is complex and encompasses a multidisciplinary approach. Patients in an advanced stage still have a very high mortality rate in spite of receiving optimum medical care. The development of new therapeutic techniques that afford a better prognosis has therefore been essential. Of these, and leaving aside surgical treatments, myocardial regeneration by means of cellular therapy, new concepts in tissue engineering and their results, and the applications of new advances in the field of immunomodulation have all recently experienced development. In this article, the aim is to bring the latest concepts in the physiopathology and humoral response of cardiac failure up to date as well as doing the same with the therapeutic approaches in this area.     

Activities of daily living in people with lower limb amputation: outcomes of an intervention to reduce dependence in pre-prosthetic phase

Purpose: The main objective was to assess the change in the functional independence in basic activities of daily living (ADL) following a pre-prosthetic intervention in people with lower-limb amputation (LLA). Secondary objectives were to identify the factors contributing to the success of this intervention, and to analyze the effects on the presence of unmet needs for home adaptation.

Method: The ADL intervention was early and pre-prosthetic; it was focused on six self-care activities. Fifty-two adults with LLA, who required assistance in self-care, were included. Functional independence (Barthel) was assessed at baseline and after intervention (T2). Successful intervention was defined as independent performance of all self-care activities.

Results: There was a significant improvement in Barthel scores between baseline and T2 in toileting (p?p?p?p?p?=?0.025). The proportion of homes with an unmet need for adaptation decreased significantly in bathroom (p?=?0.008) and other internal areas (p?=?0.031). Intervention was successful for 61.5% of participants. In a multivariate model, age was significantly associated with successful intervention (OR 0.66, 95%CI 0.52–0.83).

Conclusions: A short and pre-prosthetic ADL intervention improves functional independence and reduces the need for home adaptation. ADL programs should be included in rehabilitation strategies.

• Implications for Rehabilitation

• Because basic activities of daily living (ADL) can be seriously compromised after a lower-limb amputation, it is important for this population to improve or maintain their level of independence.

• A short and pre-prosthetic ADL intervention is an effective method for an early recovery of functional independence in self-care activities and promotes home adaptation.

• Age is an important determinant of functional recovery, and most subjects can achieve independence in basic ADL regardless of the level of amputation.

• A pre-prosthetic ADL program should be included in rehabilitation strategies for adults with lower-limb amputation.

     

Mechanical elongation of astrocyte processes to create living scaffolds for nervous system regeneration

Following brain injury or neurodegenerative disease, successful regeneration requires orchestrated migration of neurons and reformation of long‐distance communication fibres, or axons. Such extensive regeneration does not occur in the mature brain; however, during embryonic development, pathways formed by glial cells extend several millimeters (mm) to create ‘living scaffolds' for targeted neural cell migration and axonal pathfinding. Techniques to recapitulate long process outgrowth in glial cells have proven elusive, preventing the exploitation of this developmental mechanism for regeneration. In the current study, astrocytes were induced to form a network of interconnected processes that were subjected to controlled mechanical tension in vitro using custom‐built mechanobioreactors. We discovered a specific micron (μm)‐scale mechanical growth regime that induced elongation of the astrocytic processes to a remarkable length of 2.5 mm at an optimal rate of 12.5 μm/h. More rapid mechanical regimes (> 20 μm/h) caused greater incidence of process degeneration or outright breakage, whereas slow regimes (< 4 μm/h) led to adaptive motility, thus failing to achieve process elongation. Cellular phenotype for this astrocytic ‘stretch‐growth’ was confirmed based on presentation of the intermediate filament glial fibrillary acidic protein (GFAP). Mechanical elongation resulted in the formation of dense bundles of aligned astrocytic processes. Importantly, seeded neurons readily adhered to, and extended neurites directly along, the elongated astrocytic processes, demonstrating permissiveness to support neuronal growth. This is the first demonstration of the controlled application of mechanical forces to create long astrocytic processes, which may form the backbone of tissue‐engineered ‘living scaffolds' that structurally emulate radial glia to facilitate neuroregeneration. Copyright © 2016 John Wiley & Sons, Ltd.     

Adult stem cells and heart regeneration

Cardiovascular disease remains the single greatest cause of death in the Western world, claiming more lives in the USA than the next four leading causes combined. Among these diseases, the incidence of heart failure continues to rise at a staggering rate. Recent advances in medical and device therapies have dramatically improved both the survival and quality of life of many of these patients; however, limited strategies are available to address the central pathophysiology underlying the development of heart failure, namely, the loss of functional cardiomyocytes. Therefore, one recent strategy has been the development of cell-based therapies, aiming towards the replacment of injured or lost cardiomyocytes and thereby improved cardiac function. In this review, we will examine the cell types undergoing investigation as potential cell-based therapies and provide an overview of current clinical trials utilizing cell-based therapeutic approaches in patients with heart disease.     

Adipose-derived stem cells for the regeneration of damaged tissues

As the promise of stem cell-based therapies begins to be realised, and efforts to bring advances to the clinic mount, the source of these cells is increasingly important. The morbidity associated with harvesting stem cells from solid organs and the invasive nature of bone marrow biopsies may limit their practicality for wider clinical applications. An emerging body of literature suggests that adipose tissue may provide an abundant, readily accessible source of cells with similar potential to that described of other adult stem cells. This review will address advances in the use of adipose stem cells in fields as divergent as soft tissue reconstruction and cerebral infarction recovery. Numerous challenges will also be discussed; however, rapidly accumulating advances suggest that adipose stem cells may be as effective as they are abundant.     

Progenitor and stem cells for bone and cartilage regeneration

Research in regenerative medicine is developing at a significantly quick pace. Cell‐based bone and cartilage replacement is an evolving therapy aiming at the treatment of patients who suffer from limb amputation, damaged tissues and various bone and cartilage‐related disorders. Stem cells are undifferentiated cells with the capability to regenerate into one or more committed cell lineages. Stem cells isolated from multiple sources have been finding widespread use to advance the field of tissue repair. The present review gives a comprehensive overview of the developments in stem cells originating from different tissues and suggests future prospects for functional bone and cartilage tissue regeneration. Copyright © 2009 John Wiley & Sons, Ltd.     

Matrilin‐3 codelivery with adipose‐derived mesenchymal stem cells promotes articular cartilage regeneration in a rat osteochondral defect model

Matrilin‐3 is an essential extracellular matrix component present only in cartilaginous tissues. Matrilin‐3 exerts chondroprotective effects by regulating an anti‐inflammatory function and extracellular matrix components. We hypothesized that the codelivery of matrilin‐3 with infrapatellar adipose‐tissue‐derived mesenchymal stem cells (Ad‐MSCs) may enhance articular cartilage regeneration. Matrilin‐3 treatment of Ad‐MSCs in serum‐free media induced collagen II and aggrecan expression, and matrilin‐3 in chondrogenic media also enhanced in vitro chondrogenic differentiation. Next, the in vivo effect of matrilin‐3 codelivery with Ad‐MSCs on cartilage regeneration was assessed in an osteochondral defect model in Sprague Dawley rats: Ad‐MSCs and hyaluronic acid were implanted at the defect site with or without matrilin‐3 (140, 280, and 700 ng). Safranin O staining revealed that matrilin‐3 (140 and 280 ng) treatment significantly improved cartilage regeneration and glycosaminoglycan accumulation. In the animals treated with 140‐ng matrilin‐3, in particular, the defect site exhibited complete integration with surrounding tissue and a smooth glistening surface. The International Cartilage Repair Society macroscopic and O'Driscoll microscopic scores for regenerated cartilage were furthermore shown to be considerably higher for this group (matrilin‐3; 140 ng) compared with the other groups. Furthermore, the defects treated with 140‐ng matrilin‐3 revealed significant hyaline‐like cartilage regeneration in the osteochondral defect model; in contrast, the defects treated with 700‐ng matrilin‐3 exhibited drastically reduced cartilage regeneration with mixed hyaline–fibrocartilage morphology. Codelivery of matrilin‐3 with Ad‐MSCs significantly influenced articular cartilage regeneration, supporting the potential use of this tissue‐specific protein for a cartilage‐targeted stem cell therapy.     

New frontiers of retinal therapeutic intervention: a critical analysis of novel approaches

A recent wave of pharmacologic and technologic innovations has revolutionized our management of retinal diseases. Many of these advancements have demonstrated efficacy and can increase the quality of life while potentially reducing complications and decreasing the burden of care for patients. Some advances, such as longer-acting anti-vascular endothelial growth factor agents, port delivery systems, gene therapy, and retinal prosthetics have been approved by the US Food and Drug Administration, and are available for clinical use. Countless other therapeutics are in various stages of development, promising a bright future for further improvements in the management of the retinal disease. Herein, we have highlighted several important novel therapies and therapeutic approaches and examine the opportunities and limitations offered by these innovations at the new frontier.

KEY MESSAGES

• Numerous pharmacologic and technologic advancements have been emerging, providing a higher treatment efficacy while decreasing the burden and associated side effects.
• Anti-vascular endothelial growth factor (anti-VEGF) and its longer-acting agents have dramatically improved visual outcomes and have become a mainstay treatment in various retinal diseases.
• Gene therapy and retinal prosthesis implantation in the treatment of congenital retinal dystrophy can accomplish the partial restoration of vision and improved daily function in patients with blindness, an unprecedented success in the field of retina.

     

New cell therapies in cardiology

Even today, cardiovascular disease remains the leading cause of death globally. Cardiological conditions such as myocardial infarction, ischemic injury and chronic cardiomyopathy result in permanent cardiac tissue damage followed by heart failure. Current therapies primarily aim to trigger the pathological remodeling that occurs after cardiac injury and also to reduce risk factors involved in cardiovascular diseases. Animal model studies over the last decade indicate that the systematic administration of autologous and allogeneic stem cells possesses therapeutic potential to improve overall cardiac functions. This evidence robustly indicates that cardiac tissue has the potential to undergo a systematic repair process. The past few years have also witnessed a splurge in clinical research that particularly aims to explore the regenerative properties of the naive stem cells to restore cardiac functions. The mechanisms involved in stem cell therapy remain unclear. The magnitude of benefit demonstrated in animal models is yet to be completely translated into humans. The future of cardiac research will require tangible synchrony between clinicians and basic scientists to unravel the precise mechanism of stem cell therapy. It is also pivotal to define an ideal cell type and a suitable cell delivery technique that provide maximum benefit, while eliminating the grey areas in translational cardiology research. In this article, the authors review the properties and therapeutic potential of the stem cell plethora reported for cardiac repair and regeneration, recent stem cell therapies, mode of action, their delivery techniques, recent clinical developments and the future for these stem cell therapies in cardiology.     

Cell sheet engineering and its application for periodontal regeneration

Periodontitis is a inflammation induced by a bacterial infection that causes the destruction of the attachment apparatus of dental roots. Several materials, such as bone graft materials, barrier membranes and protein products have been developed and used to treat periodontal defects clinically; however, it is difficult to regenerate the complete periodontal tissue structure. Recently, cytotherapeutic approaches have been introduced to overcome the limitation of conventional procedures. The in vitro‐expanded autologous cells derived from several kinds of tissues have already been used in several clinical trials. These cytotherapeutic treatments have been shown to be safe and effective for the treatment of periodontitis. Our strategy has been to integrate stem cell biology and cell sheet engineering, in which a temperature‐responsive intelligent polymer is grafted onto the surface of cell culture dish to create a ‘cell sheet’, to achieve a novel treatment method for periodontitis. By simple reduction of the temperature to below 32°C, a contiguous cell sheet, which is capable of keeping extracellular matrix proteins and cell–cell interactions intact, can be harvested for transplantation without the use of scaffolds. This technology has already been employed in clinical trials, confirming the safety and efficacy of the treatment. In this review, we introduce recent progress in the engineering of cell sheets and review the potential of cell sheet technology for periodontal regenerative medicine. Copyright © 2013 John Wiley & Sons, Ltd.     

Adult acquired major upper limb amputation in Norway: prevalence,demographic features and amputation specific features. A population-based survey

Purpose.?To estimate the prevalence of adult acquired major upper limb amputation in Norway. To describe this amputee population regarding demographic features and amputation specific features. To compare our data to data collected internationally.

Method.?Population-based cross-sectional study on adult upper limb amputees with acquired limb loss through or proximal to the radio-carpal joint. Patients were found in the databases of the two companies in Norway that make upper limb prostheses and in the medical records of three of the largest Norwegian hospitals. Data were collected by postal questionnaires.

Results.?We estimated a population prevalence of 11.6 per 100,000 adults (n == 416). Our survey was not 100%% comprehensive and the estimate is conservative. The amputees were predominantly men with traumatic, unilateral, distal amputations at a young age. There were significant gender- and amputation level differences in cause. Most amputees had used prostheses. About four in ten were in paid employment.

Conclusions.?Our findings are mainly consistent with earlier studies from other countries. Implications of our findings related to the planning of future health care for these patients are outlined, including suggestion of regional multidisciplinary rehabilitation emphasising occupational rehabilitation and focus on preventive measures. Potential areas of follow-up are suggested.