Animal studies for treating stress urinary incontinence based on cell therapy.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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Comprising nearly 50% of the human body [1] skeletal muscles compose the machinery that sets the body in movement. When well-trained, muscles have the capability to protect joints and bones from daily waste and trauma [2]. They hold an intrinsic protective mechanism against cancer formation and metastasis settling [3] and are at the same time the main energy reservoir of the body storing more than 80% of our glycogen reserve [4]. Hence, muscle tissue is associated to several functions and networks with different parts of the body. It is composed of muscle fibers, the contractile units, which are bound together by connective tissue. Most importantly, skeletal muscles display an astonishing regenerative capacity [5]. Due to resident stem cells, one week after severe trauma new myotubes are already being formed, and within 28 days after trauma muscle regeneration is almost complete [6]. These intrinsic features turn the skeletal muscle into a very interesting topic of study in regenerative medicine. Taking advantage of the regenerative potential of stem and precursor cells, skeletal muscle is constantly renewed in response to injury, damage or aging. It is this natural process that researchers are about to harness in order to help patients with many muscle diseases and diseases that causes weakness or destruction of the muscle - for instance stress urinary incontinence (SUI), muscular dystrophy. In this chapter, the focus will be on the regeneration of the skeletal muscle and especially in the case of incontinence. Urinary incontinence is the involuntary loss of urine and is a major medical problem affecting millions of people worldwide. It impairs the quality of life of patients and involves high healthcare costs. The main reason provoking SUI is the damage of the sphincter muscle due to childbirth, surgical treatments (as prostatectomy) or as an effect of aging. Current treatment encompasses behavioral training, pelvic floor exercising, drugs, medical devices and surgery. Unfortunately, all these options permit only limited recovery: short-term relief and are often accompanied with complications. The ultimate goal will be to prevent disease progression and to restore the tissue and its functions.
Stem cell therapy as a treatment for skeletal muscle diseases is becoming a reality and it represents a promising alternative for muscle regeneration and for treating SUI in a more complete and definitive manner.
In this chapter, the homeostasis and maintenance of skeletal muscle is explained in order to understand the basis behind muscle regeneration. As different types of stem cells have been demonstrated to form fibers and to develop into skeletal muscle, cell sources for a muscle cell therapy is discussed. Some of them have also been applied successfully in preclinical and clinical studies that are going to be described. Finally, we are going to highlight the parts important for the translational effort into clinics including biomaterials, cell delivery, imaging, regulatory affairs, and manufacturing.
The secret of skeletal muscle staggering regenerative capacity is found in the specific components of its cell niche. The muscle tissue is composed of long and slender cells that form muscle fibers grouped in bundles (Figure 1). Adjacent to these myofibers, a heterogeneous pool of subsarcolemmal progenitor and stem cells known as muscle satellite cells (SC), respectively committed to myogenic differentiation or to self-renewal, guarantee a fast and efficient regenerative process after trauma [7]. These cells, activated by injury [8], work hierarchically to maintain the in situ pool of cells (Figure 1) and to reconstruct damaged tissue in less than one month by differentiating into new myotubes.
The muscle niche is the secret of skeletal muscle astounding regenerative capacity. Attached to bones, skeletal muscle are organs composed of skeletal muscle tissue, connective tissue, nerves and blood vessels. Each individual skeletal muscle is composed by hundreds or thousands bundles of muscle fibers that are single cylindrical muscle cells. (A) The connective tissue surrounding each muscle is called epimysium, and its projections that separe muscle bundles are called perimysium. (B) The connective tissue between single muscle fibers is called endomysium and servers as the muscle satellite cells (SCs) niche. SCs are subsarcolemmal cells that can be activated to regenerate new muscle fibers. (C) Skeletal Muscle tissue is not only formed by muscle fiber, but also by acellular matrix, cellular components, blood and lymphatic vessels and nerves. Altogether, these muscle niche components play a distinct role on muscle regeneration and on muscle progenitor cell regulation.
After trauma an inflammatory infiltrate can be observed when neutrophils, macrophages, satellite cells and later myoblasts work chronologically together cleaning up damaged fibers and reconstructing new functional myotubes. Neutrophils are the first cells to arrive at the site of injury, followed by macrophages three hours after damage [6]. Through the combined action of free radicals, growth factors and chemotactic factors these inflammatory cells contribute both to injury and repair [9]. Without the neutrophil-related oxidative and proteolytic modifications of damaged tissue, phagocytosis of debris would not be possible [10]. Macrophages are the major housecleaners that remove remaining debris of fibers. Furthermore, macrophages produce proteases to lyse the sarcolemma membrane, which allows activation and proliferation of SC [11]. Dismantling of the extracellular matrix is key to SC activation, and the up-regulation of metalloproteinase is required for muscle regeneration [12]. Macrophage infiltration is also important for SC activation and proliferation by activating NF-κB via TWEAK ligand [13]. Quiescent SCs are still found between the basal membrane and sarcolemma until the third day after injury. Subsequently, they are slowly replaced by cells with large nuclei, nucleoli, and cytoplasmatic processes filled with ribonucleoprotein granules. These myoblasts display an initial exponential growth phase and after the seventh day they start to form myotubes with centrally placed nuclei and peripheral myofibrils. On the periphery of these newly formed myotubes a new population of subsarcolemmal quiescent cells replenishes the SC pool [6]. Finally, mature myofiber nuclei do not display mitotic figures throughout the regeneration process, demonstrating that the damaged fiber cannot heal itself without the activation of satellite cells.
Components of the muscle niche are important for skeletal muscle regeneration and satellite cell activation. The basal lamina is the common anatomic site of satellite cells and also contributes to cell fate. The basal lamina is rich in α7β1 integrin which acts directly in the anchorage, adhesion and quiescence of satellite cells [14]. These integrin functions also comprise the migration and proliferation of developing myoblasts [15], the formation and integrity of neuromuscular junctions [16], as well as the binding of muscle fibers. Another integrin, VLA-4, is expressed as myotubes form and influences the alignment and fusion of myoblasts [17]. Finally, the calcium-dependent cell adhesion protein M-cadherin is a morphoregulatory molecule facilitating myoblast fusion and cell adhesion to its adjacent myofibers [18, 19].
The surrounding acellular matrix (ACM) contains a number of components that can influence the behavior and regulate the growth of muscle progenitor cells. The ACM is a source of hepatocyte [20] and fibroblast [21] growth factors, which act on the activation of satellite cells, proliferation and inhibition of differentiation. Another factor produced by the ACM is the endothelial growth factor, which promotes satellite cell activation and cell survival after injury [22]. Finally, the aged ACM is capable of impairing the regenerative potential of satellite cells and inducing fibrosis by activating the Wnt signaling pathway [23].
Fibroblasts are the main source of collagen in the muscular interstitial space [24]. They continuously promote the formation of the basal lamina during myogenesis [25] and after muscle injury proliferate hand in hand with Pax7 positive satellite cells, orchestrating the fine balance between muscle reconstruction and fibrosis formation [26]. These fibroblasts prevent premature activation and differentiation of muscle progenitor cells, thereby avoiding depletion of the pool of satellite cells. Accordingly, satellite cells are sufficient to regulate the ingrowth of fibroblasts and fibrosis formation [26]. Fibroblasts are also involved in myosin switch from fetal to adult muscle, specially promoting Myosin Heavy Chain type 1 expression (slow twitch) in several limb muscles in the fetal mouse and in the soleus in the adult muscle [27].
Circulating and locally produced soluble factors participate in the signaling pathway that regulates satellite cell activity. During exercise and stretching muscle fibers liberate hepatocyte growth factor (HGF) through nitric oxide stimulation and induce activation of satellite cells [28]. HGF can also activate satellite cells by activating the sphingolipid signaling cascade upon disruption of the laminin-integrin adhesion in the event of trauma [29]. Furthermore, the insulin-like growth factor 1 (IGF-1), a potent mitogen produced locally during muscle hypertrophy and injury, can induce activation, proliferation and differentiation of satellite cells [8, 30]. In contrast, mysotatin, a growth differentiation factor and member of the TGF-beta protein family secreted by adult skeletal muscle, is capable of inhibiting activation and self-renewal of quiescent cells [31]. Finally, a hormone produced by the thyroid gland and responsible for inducing hypercalcemia named Calcitonin [32], has been associated with delay of satellite cell activation [33]. Together all these components and products of the muscle niche are key regulators of all the development and regeneration processes of skeletal muscle.
Exercise is capable of activating muscle gene transcription within seconds and these molecular responses can last for hours even after exercise cessation [34]. During endurance exercise, muscle consume large amounts of oxygen to generate energy by breaking down carbohydrates and posteriorly fat [35]. Muscle fibers are not in a smooth continuous muscle contraction during exercise, but rather act as a series of small groups of fibers contracting at the same time [36]. This occurs due to stimulation of neuromuscular junctions of terminal branches of axons whose cell body is in the anterior horn of the spinal cord. Altogether, these nerve and muscle components comprise the motor unit [37] and conduce impulses that enable sharp muscle contraction within milliseconds [38]. A signaling pathway is then activated by rapamycin kinase (mTOR) leading to hypertrophic changes in muscle mass [39]. The opposing effect is found during starvation when the AMP-activated protein kinase (AMPK) is switched on to up-regulate energy-conserving processes and ultimately induce muscle atrophy [39]. However, exercise is sufficient to increase the pool of stem cells reversing the effects of atrophy after prolonged limb immobilization [40].
After a trauma or during exercise nitric oxide is liberated and modulates the activation of satellite cells [41, 42]. Another evidence of this cell addition during exercise is the decrease of telomeres length detected in marathon runners, which correlates to their running hours [43]. Endurance exercise has been reported to stimulate the production of free radicals like nitric oxide [44], which has been shown to again induce activation of satellite cells thereby increasing muscle turn-over [28]. On the other hand, during muscle atrophy caused by limb immobilization an apoptotic decrease of myonuclei occurs [45] associated with a decrease in mitotic activity of satellite cells [46]. These findings underline the involvement of satellite cells in the regulation of muscle mass during exercise.
A transcriptional network controls progression of both embryonic and adult muscle stem cells [47]. Quiescent muscle embryonic progenitor cells can be identified by the co-expression of the paired-domain transcription factors Pax3 and Pax7 (Figure 2) and are maintained as a self-renewing proliferative population [48]. During embryogenesis Pax3 is required to maintain muscle progenitor cells in the somite and further induce cell migration to the required site of skeletal myogenesis [49]. Indeed the normal expression of Pax3 seems to be decisive for the development of normal muscle, and its mutation promotes malignant growth and induces tumorigenesis in alveolar rhabdomyosarcoma tumor cells [50]. However, its down-regulation is necessary for final cell commitment to myogenesis and leads to rapid and robust entry into the myogenic differentiation program [49]. The expression of transcription factor Pax7 is detectable in cells starting from the embryonic muscle progenitor to the quiescent and activated satellite cells (Figure2). Its induction in muscle-derived stem cells induces satellite cell specification by restricting alternate developmental programs [51].
Myogenic cell characterization and culture. Myogenic cell lineage can be identified in each differentiation state and pursue tightly regulated proliferation and differentiation cycles. From the embryonic state until the terminal differentiation into muscle fibers an intricate network of transcription factors regulates the fate of muscle progenitor cells. These cells can be isolated from any skeletal muscle tissue, grown in culture and reimplanted into a damaged muscle to promote muscle regeneration.
Specific molecular markers have been demonstrated to distinguish between activated and quiescent SC. Quiescent satellite cells express the transcription factor Pax7, after activation in co-expression with MyoD [52]. This dual expression is followed by a proliferative phase, down-regulation of Pax7 and terminal differentiation. If Pax3 and Pax7 down-regulation do not occur in vitro differentiation is blocked [53, 54]. In this context microRNAs (miRNAs) play a regulatory role conferring robustness to developmental timing by posttranscriptional repression of genetic programs of progenitor and satellite cells [55]. They allow rapid gene program transitions from proliferation to differentiation, blocking PAX3 [56] and Pax7 [57] activity in progenitor and satellite cells.
This interplay during development is required to ignite the commitment of satellite cells to the myogenic program, to activate the myogenic regulatory factors Myf-5 and MyoD and to promote terminal muscle differentiation [55] [58] [59], which are decisive to subsequent myoblast cell cycle progression or exit into differentiation. Through the action of the myogenic regulatory factors (MRFs), Myf5 and MyoD, the muscle progenitor cells (Pax3+) and quiescent satellite cells (Pax3+/Pax7+) become muscle lineage committed and activated myoblasts [60]. They express Myf5 and Mrf4 and rapidly give rise to Desmin+ cells, whose differentiation is regulated by myogenin, MyoD and MRF4 [61]. Completing these regulatory features, MyoD is also a main player in the intricate epigenetic cascade that controls skeletal myogenesis [62].
Several types of cell populations have been identified as potentially efficient in muscle regeneration, especially in cell therapy. They are able to self-renew, proliferate and form muscle fibers. Among these cells some are muscle derived and some are from other origin.
Muscle satellite cells, which are squeezed between the plasma membrane and basement membrane of muscle fibers, are the natural source of muscle regeneration during homeostasis or after injury in postnatal stages [63]. They are specifically expressing the paired box transcription factor pax7 [51] and have been shown to be efficient in the muscle regeneration process. One study illustrated that as little as seven satellite cells were able to generate more than 100 muscle fibers in irradiated muscle [64]. Though, satellite cells isolated from different muscles are not equivalent: they produce muscle fibers with variable contractile abilities depending on the muscle of origin [65]. This can be explained by the fact that a satellite cell pool does not seem to consist of a homogeneous population of cells [66-70]. Once activated, satellite cells are triggered toward proliferation and differentiation by giving rise to muscle precursor cells that fuse and form skeletal muscle fibers [71]. The two techniques used to isolate muscle precursor cells are selection of single fibers that are cultured or mechanical processing of muscle biopsies and enzymatic treatment with a mixture of collagenase and dispase [64, 72-74]. The first method is claimed to be less aggressive and to better preserve the cells.
Another type of cells is isolated from muscle biopsies through a series of preplating stages. These cells are also recognized to have a myogenic profile and are capable to fuse and form skeletal muscles fibers. They are known as muscle-derived stem cells (MDSC) with characteristics of non-committed progenitor cells [75, 76] and are most probably originating from blood vessel walls [77]. Similarly, other cells types isolated from the muscle compartment such as mesoangioblasts and pericytes are involved in the muscle regeneration but are of non-myogenic origin. These are vessel-associated progenitors, not expressing myogenic markers such as Myf5 and MyoD even though they can differentiate to myotubes and fuse to form fibers [78-80]. More cell types with non-myogenic profile are found in the skeletal muscle and have recently been demonstrated to form fibers. Hence, skeletal myogenic precursors or muscle stem cells sorted by FACS are capable to reconstitute fibers in rodent models [72, 81]. The first type of cells is characterized by expression of β1-integrin (adhesion protein) and CXCR4 (SDF-1 receptor), the second type by α7-integrin (adhesion protein) and CD34 markers. Side populations are also isolated from muscle tissues and are expressing specific surface markers [82]. They are distinct from satellite cells and have been used successfully in muscle regeneration in rodent models [83-87]. Surprisingly, more types of cells of the skeletal muscle tissue can contribute to muscle regeneration. In fact, recently, a new type of myogenic cells, localized in the area of the interstitium between muscle fibers, has been characterized and is known as PW1-interstitial cells (PICs). They are characterized as positive for cell stress mediator PW1 but negative for Pax7; though they possess myogenic profile in vitro and lead to muscle regeneration in vivo, which includes the generation of satellite cells [88]. Hence, various types of cells isolated from skeletal tissue either mechanically or by flow cytometry are capable to regenerate muscle. In addition to the muscle there are more sources of stem/precursor cells isolated from other compartments.
Mesenchymal stem cells (MSC) are procured from bone marrow biopsies and are multipotent stem cells that give rise also to skeletal muscle fibers and participate to restore the satellite cell niche [89]. These cells are well characterized and involved in many different applications due to their multipotency as it is the case for adipose-derived stem cells (ADSC). The latter are easily harvested by liposuction, cultured in vitro and injected to restore muscle in the case of SUI [90, 91]. Embryonic stem cells, induced pluripotent stem cells and umbilical cord blood have been demonstrated to be good alternatives for skeletal muscle regeneration [74, 92, 93]. However, precaution should be taken when these types of cells are considered for further development in clinics, as different types of viruses are used during the process of myogenic induction. In addition, there are still potential tumorigenicity issues with this sort of cells that need to be solved before further clinical application.
Hence, the sources of stem/progenitor cells for skeletal muscle regeneration are large. Though, several important factors need to be considered when choosing the optimal source for treating patients. Autologous cell therapy avoids immunogenic reaction and therefore complications after the implantation procedure. Therefore, autologous satellite/muscle precursor cells are advantageous for muscle regeneration. They are committed to muscle restoration and therefore the most convenient cells for applications in cell therapy. Their dedication to one lineage offers an advantage over other, previously discussed sources, which are multipotent and hence differentiate also into non-muscular tissue cells. Furthermore, satellite / muscle precursor cells can be isolated in a simple procedure and are easily expanded in a GMP facility. They produce enough cells to be injected after 2-3 weeks, which is much faster than the 5 - 6 weeks required for muscle derived stem cells. For allogenic application, mesenchymal and adipose derived stem cells represent valid alternatives when satellite cells cannot be extracted from the skeletal muscle.
Several animal studies have been addressing the problem of stress urinary incontinence (SUI) and different strategies have been tested to restore continence, either by applying pharmacological therapies, bulking agents, sling surgical procedures or cell-based therapies [94]. Until now, the first three strategies mentioned above are commonly applied in clinics. However, the outcomes are associated with adverse events and limited effectiveness in middle and long terms [95-97]. Therefore, cell-based therapies are aiming to bring new solutions to the treatment of SUI. Numerous preclinical studies have been implementing stem/progenitor cell injections for restoration of muscle contraction in SUI. Animal models that mimic SUI are crucial for the understanding of effects and benefits of the different therapies options.
To stimulate SUI in animals, various methods were applied. The goal is to injure one or several aspects of the urinary continence mechanisms to provoke incontinence as found in patients. The methods comprise the compression of the muscular and neurological system involved in continence by vaginal distension [98, 99], crush of the pudental nerve [100], damaging of anatomic supports such as fascia and pubourethral ligament [101-104] or destruction of intrinsic urethra by periurethral cauterization, urethral sphincterectomy, pudendal nerve transection and botulinum toxin periurethral injection [105-112]. One has to note that vaginal distension or pudendal nerve injury are relatively limited models due to the fact that the injury is naturally recovered after 2 weeks and thereby does not mimic an irreversible SUI. Eberli et al. have been describing a large animal model for SUI that was followed for 6 months. In this study, the sphincter muscle of dogs has been irreversibly damaged by surgically removing part of it. During the follow-up, the dogs were permanently affected by this procedure with long term decrease in sphincter pressures [107].
Rats are the preferred animal models for studying safety and efficacy of several cell types for treatment of SUI (table.1).
\n\t\t\t\tCell type\n\t\t\t | \n\t\t\t\n\t\t\t\tAnimal model\n\t\t\t | \n\t\t\t\n\t\t\t\tSUI model\n\t\t\t | \n\t\t\t\n\t\t\t\tInjectionTarget organ\n\t\t\t | \n\t\t\t\n\t\t\t\tTime pointWeeks\n\t\t\t | \n\t\t\t\n\t\t\t\tReference\n\t\t\t | \n\t\t\t\n\t\t\t\tYear\n\t\t\t | \n\t\t
MDSC | \n\t\t\tSCID mice / Rats | \n\t\t\tCryoinjury bladder | \n\t\t\tBladder | \n\t\t\t1 to 4 | \n\t\t\tHuard et al. | \n\t\t\t2002 | \n\t\t
MPC | \n\t\t\tMice | \n\t\t\tNoxetin | \n\t\t\tUrethral | \n\t\t\t2 to 4 | \n\t\t\tYiou et al. | \n\t\t\t2002 | \n\t\t
MDSC | \n\t\t\tRats | \n\t\t\tSciatic nerve section | \n\t\t\tUrethral | \n\t\t\t4 | \n\t\t\tLee et al. | \n\t\t\t2002 | \n\t\t
MDPC | \n\t\t\tRats | \n\t\t\tSciatic nerve section | \n\t\t\tUrethral | \n\t\t\t2 | \n\t\t\tCannon et al. | \n\t\t\t2003 | \n\t\t
MPC | \n\t\t\tRats | \n\t\t\tElectrocoagulation | \n\t\t\tUrethral | \n\t\t\t0.7 to 4 | \n\t\t\tYiou et al. | \n\t\t\t2003 | \n\t\t
MDSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tUrethral | \n\t\t\t12 | \n\t\t\tLee et al. | \n\t\t\t2004 | \n\t\t
MDC | \n\t\t\tRats | \n\t\t\tElectrocauterization | \n\t\t\tUrethral | \n\t\t\t2 to 6 | \n\t\t\tChermansky et al. | \n\t\t\t2004 | \n\t\t
MDSC | \n\t\t\tRats | \n\t\t\tSciatic nerve section | \n\t\t\tUrethral sling | \n\t\t\t2 | \n\t\t\tCannon et al. | \n\t\t\t2005 | \n\t\t
MDC fibroblasts | \n\t\t\tRats | \n\t\t\tSciatic nerve section | \n\t\t\tUrethral | \n\t\t\t4 | \n\t\t\tKwon et al. | \n\t\t\t2006 | \n\t\t
Myoblasts | \n\t\t\tRats | \n\t\t\tCryoinjury / noxecin | \n\t\t\tUrethral | \n\t\t\t1 to 6 | \n\t\t\tPraud et al. | \n\t\t\t2007 | \n\t\t
Myofibers | \n\t\t\tPigs | \n\t\t\tUrethral injury | \n\t\t\tMyofiber implantation | \n\t\t\t4 | \n\t\t\tLecoeur et al. | \n\t\t\t2007 | \n\t\t
MDSC_FACS sorted | \n\t\t\tRats | \n\t\t\tNerve transection / sphincter injury | \n\t\t\tUrethral | \n\t\t\t4 to 12 | \n\t\t\tHoshi et al. | \n\t\t\t2008 | \n\t\t
ADSC | \n\t\t\tRats | \n\t\t\tVaginal dilatation | \n\t\t\tUrethral | \n\t\t\t4 | \n\t\t\tLin et al. | \n\t\t\t2010 | \n\t\t
BMSC | \n\t\t\tRats | \n\t\t\tSciatic nerve section | \n\t\t\tUrethral sling | \n\t\t\t4 to 12 | \n\t\t\tZou et al. | \n\t\t\t2010 | \n\t\t
BMSC | \n\t\t\tRats | \n\t\t\turethrolysis / cardiotoxin | \n\t\t\tUrethral | \n\t\t\t13 | \n\t\t\tKinebuchi et al. | \n\t\t\t2010 | \n\t\t
MDSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tUrethral | \n\t\t\t1 to 4 | \n\t\t\tXu et al. | \n\t\t\t2010 | \n\t\t
Myoblasts / ADSC | \n\t\t\tRats | \n\t\t\tVaginal dilatation | \n\t\t\tUrethral | \n\t\t\t4 | \n\t\t\tFu et al. | \n\t\t\t2010 | \n\t\t
UCBSC | \n\t\t\tRats | \n\t\t\tElectrocauterization | \n\t\t\tUrethral | \n\t\t\t2 to 4 | \n\t\t\tLim et al. | \n\t\t\t2010 | \n\t\t
BMSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tUrethral | \n\t\t\t4 to 8 | \n\t\t\tCorcos et al. | \n\t\t\t2011 | \n\t\t
BMSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tUrethral | \n\t\t\t4 | \n\t\t\tKim et al. | \n\t\t\t2011 | \n\t\t
BMSC | \n\t\t\tRabbits | \n\t\t\tCryoinjury | \n\t\t\tUrethral | \n\t\t\t1 to 2 | \n\t\t\tImamura et al. | \n\t\t\t2011 | \n\t\t
ADSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tPeriurethral | \n\t\t\t3 to 4 | \n\t\t\tWu et al. | \n\t\t\t2011 | \n\t\t
ADSC | \n\t\t\tRats | \n\t\t\tPelvic nerve section | \n\t\t\tPeriurethral | \n\t\t\t2 to 4 | \n\t\t\tWatanabe et al. | \n\t\t\t2011 | \n\t\t
ADSC | \n\t\t\tRats | \n\t\t\tPudendal nerve section | \n\t\t\tPeriurethral | \n\t\t\t8 | \n\t\t\tZhao et al. | \n\t\t\t2011 | \n\t\t
MPC | \n\t\t\tDogs | \n\t\t\tUrethral sphincterecomy | \n\t\t\tPeriurethral | \n\t\t\t24 | \n\t\t\tEberli et al. | \n\t\t\t2012 | \n\t\t
BMSC | \n\t\t\tRats | \n\t\t\tPudendal, other nerves section | \n\t\t\tUrethra and baldder neck | \n\t\t\t1 to 8 | \n\t\t\tDu et al. | \n\t\t\t2012 | \n\t\t
MSC | \n\t\t\tRats | \n\t\t\tVaginal dilatation | \n\t\t\tintravenously | \n\t\t\t0.6 to 1.4 | \n\t\t\tCruz et al. | \n\t\t\t2012 | \n\t\t
Animal studies for treating stress urinary incontinence based on cell therapy.
Abbreviations: ADSC, adipose-derived stem cells; BMSC, bone-marrow mesenchymal stem cells; MDC, muscle-derived cells; MDSC, muscle-derived stem cells; MPC, muscle precursor cells; MSC, mesenchymal stem cells; UCBSC, umbilical cord blood stem cells;
Muscle derived cells were the first cells to be used for urethral regeneration and to demonstrate that cell therapy might represent an option for the treatment of SUI. Hence, MDSC, myoblasts, MPCs or muscle fibers injected around the injured area were surviving, participating in fiber formation and re-establishing muscle contractility [113-118]. In rat models, it was shown that the injected MDSC – isolated by preplating procedures or FACS-sorted - were participating actively in muscle regeneration for up to 3 months [119, 120]. Interestingly, in a dog study, a rare large animal model for SUI, transplanted MPCs were efficiently restoring the sphincter pressure to 80% of normal values during a half year follow-up period [121]. Concerning the speed of regeneration, Cannon et al. noticed 87% recovery after only 2 weeks post-injection and Chermansky et al. a full recovery after 4 weeks with myoblast and 6 weeks with MDSC [113, 116, 122]. Hence, muscle derived cells are able to incorporate the urethral structure and help recovering continence by reconstructing new fibers and connections with the surrounding cells – nerves, Schwan cells, vessels etc. [119, 121]. However, they are not the only kind of cells facilitating this cell therapy. Bone marrow derived mesenchymal stem cells, adipose-derived stem cells, umbilical cord blood stem cells (UCBSC) have been proven to also restore continence in animal SUI models [123-135]. In fact, different studied showed that these cells are contributing to the formation of fibers and contractile muscles which permit to control urinary leakage. When compared to common procedures for treatment of SUI such as the injection of collagen bulking agent, ADSC cell therapy provided better results [132]. Moreover, the association of cells with biomaterials seems to enable further improvements as observed with BMSC and sling systems or MDSC with fibrin glue [135, 136]. To improve this cell therapy model, Zhao et al. took account of the fact that muscle regeneration is an interaction process involving paracrine factors produced by surroundings cells and combined with ADSC the nerve growth factors. This method stimulated muscle regeneration and demonstrated that combining different cell types could be beneficial for muscle restoration in SUI.
Several clinical trials applying cell therapy in SUI have been conducted in the last decade (table.2).
\n\t\t\t\tCell type\n\t\t\t | \n\t\t\t\n\t\t\t\tSource\n\t\t\t | \n\t\t\t\n\t\t\t\tPatients / n\n\t\t\t | \n\t\t\t\n\t\t\t\tInjection \n\t\t\t | \n\t\t\t\n\t\t\t\tTarget organ\n\t\t\t | \n\t\t\t\n\t\t\t\tDeliverybiomaterial\n\t\t\t | \n\t\t\t\n\t\t\t\tTime pointMonths\n\t\t\t | \n\t\t\t\n\t\t\t\tOutcomesMeasurements\n\t\t\t | \n\t\t\t\n\t\t\t\tReference\n\t\t\t | \n\t\t\t\n\t\t\t\tYear\n\t\t\t | \n\t\t
Chrondrocytes | \n\t\t\tautologous | \n\t\t\tWomen / 32 | \n\t\t\tTrans/peri-urethral | \n\t\t\tBladder neck | \n\t\t\tcalcium alginate | \n\t\t\t12 | \n\t\t\t81% improved 50% continent | \n\t\t\tBent et al. | \n\t\t\t2001 | \n\t\t
Myoblasts and fibroblasts | \n\t\t\tautologous | \n\t\t\tWoman / 123 | \n\t\t\tTransurethral | \n\t\t\tUrethra | \n\t\t\tautologous serum collagen | \n\t\t\t12 | \n\t\t\t79% continent 13% improved | \n\t\t\tMitterberger et al. | \n\t\t\t2007 | \n\t\t
Myoblasts and fibroblasts | \n\t\t\tautologous | \n\t\t\tmen / 63 | \n\t\t\tTransurethral | \n\t\t\tUrethra | \n\t\t\tautologous serum collagen | \n\t\t\t12 | \n\t\t\t65% continent 17% improved | \n\t\t\tMitterberger et al. | \n\t\t\t2008 | \n\t\t
MDSC | \n\t\t\tautologous | \n\t\t\tWomen / 8 | \n\t\t\tTrans/peri-urethral | \n\t\t\tExternal sphincter | \n\t\t\tnone | \n\t\t\t3 to 24 | \n\t\t\t63% improved 13% continent | \n\t\t\tCarr et al. | \n\t\t\t2008 | \n\t\t
Myoblasts | \n\t\t\tautologous | \n\t\t\tBoys / 7 Girls / 1 | \n\t\t\tTransurethral | \n\t\t\tExternal sphincter | \n\t\t\tnone autologous serum | \n\t\t\t12 to 18 | \n\t\t\t88% improved 38% continent | \n\t\t\tKajbafzadeh et al. | \n\t\t\t2008 | \n\t\t
UCBSC | \n\t\t\tallogenic | \n\t\t\tWomen / 39 | \n\t\t\tTransurethral | \n\t\t\tSubmucosa | \n\t\t\tnone | \n\t\t\t12 | \n\t\t\t72% improved 9% continent | \n\t\t\tLee et al. | \n\t\t\t2010 | \n\t\t
Myoblasts | \n\t\t\tautologous | \n\t\t\tWomen / 12 | \n\t\t\tTransurethral | \n\t\t\tExternal sphincter | \n\t\t\tnone | \n\t\t\t12 | \n\t\t\t50% improved 25% continent | \n\t\t\tSèbe et al. | \n\t\t\t2011 | \n\t\t
MDC | \n\t\t\tautologous | \n\t\t\tMen / 222 | \n\t\t\tTransurethral | \n\t\t\tExternal sphincter | \n\t\t\tnone | \n\t\t\tat least 12 | \n\t\t\t12% continent 42% improved 46% no efficacy | \n\t\t\tGerullis et al. | \n\t\t\t2012 | \n\t\t
ADSC | \n\t\t\tautologous | \n\t\t\tMen / 3 | \n\t\t\tTransurethral | \n\t\t\tExternal Urethra sphincter Submucosa space | \n\t\t\tnone | \n\t\t\t6 | \n\t\t\timprovement | \n\t\t\tYamamoto et al. | \n\t\t\t2012 | \n\t\t
Myoblasts | \n\t\t\tautologous | \n\t\t\tWomen / 38 | \n\t\t\tIntrasphincteric | \n\t\t\tExternal Urethra sphincter | \n\t\t\tnone | \n\t\t\t1.5 | \n\t\t\t78.4% improved 13.5% cured 8.1% unchanged | \n\t\t\tBlagange et al. | \n\t\t\t2012 | \n\t\t
Clinical trials for treating stress urinary incontinence based on cell therapy.
Abbreviations: MDC, muscle-derived cells; MDSC, muscle-derived stem cells; UCBSC, umbilical cord blood stem cells.
Safety and efficacy of this strategy have been proven with several types of cells in women and men. As the procedures differ from one trial to another straight comparisons between them are difficult. Additionally, the recruited patients suffered from different levels of SUI - from moderate to severe- and some studies even included complementary therapies such as electrical stimulation or exercises to improve the results. Nevertheless, the results were highly promising and have demonstrated that a solution for patients suffering of SUI is within reach. Surprisingly, the first cells to be used in a clinical trial for SUI was not muscle derived cells but chondrocytes isolated from auricular cartilage that were expanded in culture before injection in female patients. Out of 32 treated patients 26 had an improved situation and 50% were continent after one year [137]. This was the only clinical study using chondrocytes for voiding dysfunction. Muscle derived cells (myoblasts and MDSC) are the most frequently used cells in muscle regeneration for SUI in both genders. Myoblasts have been used in many trials and were injected in or around the external urethral sphincter. The efficiency was stated to be between 50% and 88% in a follow-up of 12 months [138-141]. Even if the designs between studies differ, the combination of cell therapy with electrical stimulation or/and pelvic floor exercises may explain the variation between the values. In fact, a cell therapy with the application of myoblasts alone seems to provide a 50% improvement [139, 141], improving to 78.4% if electrical stimulation is added [138] and reaching 88% with pelvic floor exercises [140]. This approximate comparison can encourage future clinical studies to combine other therapies and exercises with cell therapies in order to optimize the outcome. Myoblasts have also been combined with fibroblasts mixed in a collagen solution. The results were impressive: 79% of treated women and 65% of the men reached continence [142, 143]. As a Lancet publication of this group was retracted, these results should be handled with precaution and should be confirmed by other groups [144]. Other muscle-derived cells have been injected in patients with SUI. Since 2008, MDSC have been applied in several clinical trials [145, 146] with improvement rates of 53% after 1-year follow-up with 10 million cells injected, 63% with 20 million and 67% with 50 million. The efficiency of the cell therapies seems to be dose-dependent. This was confirmed by Kaufman et al. in a 6-month dose escalating study, where improvements increased with the dose of injected cells. The best results were obtained with 200 million MDSC injected [146]. Interestingly, no serious adverse effects were observed even when numbers of UCBSC as high as 400 million were applied [147]. In this latter case, 72% of 39 patients were more than 50% satisfied 12 months post-injection. This represents another type of cells that is suitable for SUI treatment. Although the cell therapy with UCBSC is allogenic, no immunosuppressive effects were observed during this cure. As a source of multipotent stem cells, ADSC were trusted in recovering the contractility of the sphincter muscle in patients [148]. Certainly, the encouraging preclinical studies enabled transplantation of ADSC in patients suffering from SUI. However, only 3 patients were treated so far. Periurethral injection of ADSC seems to be safe and showed improvement of the sphincter contraction after 6 months follow-up. The use of total nucleated cells associates with lysates seems to be another good option for treating SUI. This type of cells significantly helped all treated patients in the study: 100% noticed improvement in their situation and 88% reached complete continence after 6 months. Hence, these clinical trials show that different sources of cells were able to improve the continence level of patients suffering from SUI.
The ability to regenerate muscle tissue from patient derived cells would have profound impact on many human diseases. Cell therapy is within reach as a novel treatment option for incontinence, reflux, vocal cord dysfunction and other muscle-related pathologies. However, the carrier used for cell delivery and the techniques used to inject the cells are still being optimized.
It has been demonstrated for more than a decade that cells injected in a saline solution carrier are able to ectopically form contractile muscle [149]. However, further studies have reported very poor cell survival rates (5-20%) associated with myogenic cell implantation without embedding into protein based carriers that support cell settling into their new niche [150, 151].
Species-specific cues play an important role in cell affinity to carriers. A previous study demonstrated advantages using collagen rather than matrigel coated dishes, boosting cell growth and differentiation potential [73]. In contrast, another study with porcine satellite cells demonstrated cell preference to matrigel coated dishes and growth decrease on collagen layers[152]. Moreover, three-dimensional (3D) matrigel coated PLGA (poly lactic-co-glycolic acid) scaffolds were capable of improving cell survival when compared to direct cell injection [153]. However, the same study failed to demonstrate a comparative improvement of matrigel coated PLGA with other cell carriers. Furthermore, matrigel has not presented advantage in vivo as a carrier for myogenic cells when compared to hyaluronic acid-photoinitiator (HA-PI) complex. It rather downgraded the quality of muscle structure and decreased the total number of new myofibers after cell injection [154].
Collagen is a main component of the natural extracellular matrix of skeletal muscle, it is therefore expected that satellite cells would have their functionality up-scaled in a collagen rich environment [155]. Combined with electrical stimulation collagen induces three-dimensional expansion of muscle precursor cells in vitro and in syngeneic recipient muscle [156]. Cell cycle analyses of engrafts implanted into a 3D collagen sponge highlighted the increment of cell fractions in proliferating phases, with 80% of cell survival [157]. In addition, the use of parallel aligned collagen nanofibers yielded good proliferation and enabled the generation of aligned cell layers [158]. Finally, grafts of myoblasts seeded into three-dimensional collagen scaffolds and implanted into injured sites in mice demonstrated improvement in muscle healing, innervation and vascularization [159]. Altogether these recent studies confirm that collagen is a very promising matrix for satellite cell ingrowth and an ideal carrier for the transplantation of myogenic cells.
The success of cell transplantation into a specific site in vivo is directly dependent of 3 key points: cell source, cell carrier and injection technique. The first two were previously discussed in this chapter. We dedicate this section to the discussion of injection techniques used so far to inject myogenic cells into a specific injury site. The application of myogenic cells was already used for the treatment of male and female patients suffering from urinary incontinence, the involuntary loss of urine that represents a hygienic and social problem [160]. Transurethral ultrasound guided injections of autologous cells isolated from limb skeletal muscle biopsies were so far the method of choice [161, 162]. This method is also standard for the injection of bulking agents like collagen in the clinical practice [163]. Finally, ultrasound guidance was also used to monitor percutaneous trans-coronary-venous transplantation of autologous myoblasts in infarcted myocardium [164, 165].
Recently magnetic resonance imaging (MRI) has gained attention as a useful tool for guidance during injection of drugs and potentially of cells [166]. Pulsed focused ultrasound is a new ultrasound technique that associated with magnetic resonance guidance was recently suggested as a new imaging modality that may be utilized to target cellular therapies by increasing homing to areas of pathology [167]. It has also been demonstrated to increase drug uptake into a specific target in the prostate [168] and brain [169]. This same technique has been shown to facilitate the delivery of neural stem cells into a specific site in the brain [170]. Overall, the most successful deliveries of myogenic cells have been done either operatively in 3D scaffolds or in collagen carrier that facilitates cell settling into the new cell niche. Ultrasonography is still the most adaptable and widely used imaging technique allowing visualization of the injury zone and real time needle guidance. However, new approaches combining MRI and ultrasonographic pulses are very promising methods that need to be further studied and adapted for cell injection in different anatomic sites. Moreover, MRI is used in tracking stem cells after injection [171, 172]. In fact, it is important not only to inject the cells at the right place but also to ensure that cells are not migrating to other parts and pursuing their role in regenerating the tissue of interest. Additionally, developments in MRI technology, especially in scanning technics, offer the possibility to follow the differentiation process of injected MPCs and their fate in making fibers [173].
The application of cell-based therapies is not only advancing scientifically but also regulations are adapting and including the new scientific discoveries for clinical use. The relevant health agencies all around the world are creating committees that are modifying the regulations in order to take account of these new categories of products that are cell-based. Stem cell based therapies are part of advanced therapies, which are therapies based on genes, or cells, or tissues [174]. Concerning this emerging branch of medicinal products, the regulations are new and still in development. They have their own classification, distinct from chemical and biologic drugs, transplantation organs and medical devices. Though, they can be sometimes included in these categories. In Europe, the European Medicines Agency (EMA) is in charge of improving the standards and reviewing the applications for stem cell based therapies, which are part of Advanced Therapy Medicinal Products (ATMP), and they are found in regulation (EC) N° 1394/2007 [175]. The Committee for Advances Therapies (CAT) is the body responsible within EMA of this new field of science and its approval for marketing. The goals are to protect the patient from contaminated tissues/cells, to avoid the inappropriate handling of tissues/cells and to guaranty safety and efficacy of therapies. The documents are providing a regulatory framework that is coherent with existing ones, specific to biological and chemical entities for instance. Hence, before starting any clinical trial on human, several requirements are to be fulfilled. The cell-based product needs to be grounded on a sound and solid scientific work that is confirmed in pre-clinical studies, which show its quality, safety and efficacy. During this preparation phase, CAT is available for giving advice in preparing all the relevant files for obtaining clinical trials authorization or latter for marketing authorization. Guidelines are specifying aspects of pharmacovigilance, risk management planning, monitoring, labeling, safety, efficacy follow-up and traceability. The submission process should comply with these requirements in order to receive the green light for starting clinical trials or entering the market. During product development and clinical investigations guidelines have also been adapted by CAT for stem-cell based therapies for specifications on Good Manufacturing Practice (GMP) and Good Clinical Practice (GLP) [176]. In the US, the Office of Cellular, Tissue, and Gene Therapies (OCTGT) - part of the Center for Biologics Evaluation and Research (CBER) in FDA- is responsible of the cellular therapies products [177]. They are regulated by human cells, tissues, and cellular and tissue-based products (HCT/Ps) under the authority of Section 361 of the Public Health Services (PHS) Act as well as Title 21 of the Code of Federal Regulations (CFR) part 1271 [178]. The OCTGT are making sure that the cell-based products meet safety, purity, potency and effectiveness qualifications. EMA and FDA are collaborating closely together in the Advanced Therapies Medicinal Product cluster. The development of regulatory frameworks is not equal in all countries and is independent from a state to another state. However, at the international level, regulatory agencies are working together in sharing and harmonizing the regulatory frameworks for cellular therapy products through the International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH), the Pan-American health Organization (PAHO), WHO and Asia-Pacific Economic Cooperation (APEC). This global interaction facilitates the development of the cellular therapy field and prepares in bringing the products to the markets. As the experience is right now limited in this field, this discussion panels permits to cover the different applications and cases among the countries and therefore increase the knowledge levels among the participants and the regulatory boards. In addition, it creates convergence in the development of the regulations and guidelines concerning different aspects: manufacturing, quality assurance, quality control and pre-clinical studies [179].
Therefore, the regulations and guidelines have been reviewed and adapted for some of them in order to be applied in the field of cell therapy. This paves the road for regenerating the sphincter muscle by using stem cells.
Besides, chemical drugs, medical devices and biotechnology drugs, advanced therapies are developed and offer tailored solutions for patients. These therapies are based on genes, cells or tissues.
Cell therapy for skeletal muscle is one of many therapies that are in translational phase and can be applied in near future on treating patients. As it is involving individuals’ health and the cell product is delivered to human, safety concerns are raised. In fact, cell therapy product – as an investigational or marketed one- needs to meet requirements as any medicinal product or medical device. The goal is to deliver a consistent, safe, good quality and well-defined product. Therefore, Good Manufacturing Practice (GMP) is requested for the development of cell-based product, or its production for the market, and it consists on guidelines and regulations that advertise quality principles for manufacturing biological products. These rules are covering all the processes from the biopsy up to the final product. It involves several aspects:
Quality management, buildings and facilities, the equipment, the personnel, the documentation, the materials management, the processes in production, the monitoring, the packaging and labeling, the storage and distribution, the laboratory controls.
Advanced therapies are new technology. Hence, protocols, guidelines and regulations that are used for existing medicinal product cannot be transposed literally for cell therapies and need adaptations. However, the goals stay the same: safety, quality and efficacy.
In cell therapy, the starting material represents a critical part that takes account of donor eligibility criteria including age, tissue quality, source accessibility and viral testing. For skeletal muscle cell therapy, as described above, the sources are multiple and the efficiency of most of them is good in regenerating muscle in the case of SUI.
As soon as the biopsy is received in the manufacturing site, the GMP requirements have to be followed. Hence, quality management should be applied at all production steps: processing, testing, release, storage and transport.
Manufacturing cell product necessities safe and certified raw materials and components for cell culture and preparation. In addition, upon reception to the GMP facility, the materials need to be tested in-house regarding quality and safety. Only then, the products can be released and accepted into the production area by the responsible for quality in the facility. It is highly recommended by the regulations to use supplements – as cytokines and growth factors- from human origin and therefore some adaptations are needed in the production protocols coming from the research laboratories. One of the major problems in the cell culture is to replace the fetal bovine serum (FBS). Most of the protocols are still based on this animal derived product. Recently, some efforts have been made to work with xeno-free medium by replacing FBS with human serum and platelet lysate [180]. In the case of MPCs, one of the major sources of cells for muscle cell therapy as described above, pooled human platelet lysate was demonstrated to be a good alternative to FBS [181]. Other factors are important and must be controlled as cell seeding, growth rate, differentiation process, markers expression, potency of the cells in making contractile fibers. The protocols for each step - from receiving the biopsy up to the final product -must be standardized and approved by local authorities before starting clinical trials. Standardization means that clear and details protocols should be written and followed without deviation or modifications. Quality controls are done not only for starting materials but also at critical steps in production. Quality is a key parameter that applies to all levels of the cell therapy production: building and facilities environments, equipment, production, labeling, storage and distribution. The quality unit performs all the controls to show the purity of the products, the cleanness of the environment, the maintenance of the equipment and the respect of the specifications set for obtaining a safe, effective and potent cell product. In muscle cell therapy, the cell population should have a pure or a very high percentage of cells expressing markers of skeletal cell as described above.
All the stages and elements related to the GMP facility or the production process should be documents to insure traceability of every single action. The documents should be prepared, reviewed, approved and distributed as specified in established and written procedures. All these demanding steps require qualified personnel, well-trained in working in GMP facilities. It includes good sanitation and health habits and the right skills to accomplish the work with products for cell therapy. Finally, internal and external audits are conducted regularly to verify the respect of the GMP regulations and guidelines as validated by the GMP facility and the authorities.
A decline of approximate 30% in muscle strength and 40% in muscle volume occurs between the second and seventh decades of life [182]. Also the total number of MPCs and their proliferation potential in culture gradually decrease in an age-dependent manner [183] due to apoptosis [184]. Additionally cell fate is tightly defined by the interactions with the microenvironment and the host age is of key importance, as the stem cell regenerative capacity reduces in aged niches [185]. We have reported that although human MPCs can be successfully isolated and grown from patients of all ages and genders (figure 3), both elderly and male donors provide unstable and slower growing cells in vitro with decreased contractile output in vivo [186]. Hence, a combination of stem cell and gene therapy might be needed in older patients [187, 188].
Muscle progenitor cells identification in vitro and muscle formation after transplantation in vivo. Myogenic cells isolated from the Rectus abdominis of patients undergoing abdominal surgery, grown in culture and characterized by FACS, immunohistochemistry in vitro. Tissue formation was evaluated in vivo by Hematoxilin and Eosin staining and immunohistochemistry. Function was assessed by electromyography. A: FACS analyses of cells in P2 expressing Pax 7, MyOD, desmin and upon differentiation induction Myosin Heavy Chain (MyHC). An IgG Isotype control (red curve) was used to determine the background, whereas positive cells are plotted as a green curve. Immunocytochemistry of cells in culture expressing, MyOD (B), MyHC (C), desmin (D), sarcomeric α-actinin (E) (green -Phalloidin 488, blue – DAPI, red - mM anti-IgG Cy3). Muscle cells injected subcutaneously in nude-mice revealed muscle formation in vivo (F, G, H) and contraction upon eletrical stimulation (I). HE stained (G) and labelled with sarcomeric α-actinin-Cy3 and PKH67 (H). Muscle function significantly improved over time (I), with contraction strength still increasing after 4 weeks.*p=0.015
In the context of muscle reconstruction, gene therapy is not aimed at rectifying a genetic mutation, but at boosting the myogenic potential and ultimately the muscle functionality of the injected autologous muscle cells. Two key factors have been demonstrated to improve the quality of satellite cells for transplantation: a better vascularization [189] and endurance exercise [190]. We have previously described that an angiogenic modification of muscle precursors can overcame some of the limitations of aged muscle cells [189]. For future application expanding the knowledge produced on this study and therapeutically combining it with the intrinsic adaptation effects of endurance exercise would be of major interest. In this context, studies using muscle-specific PGC-1α transgenic animals demonstrated that ectopic expression of PGC-1α in muscle seems sufficient to evoke a trained phenotype avoiding muscle atrophy [191]. Upon activation, PGC-1α in turn controls many, if not all of the adaptations of skeletal muscle to endurance exercise [192]. Hereafter, PGC-1α muscle-specific transgenic animals exhibit high endurance, oxidative muscle fibers, an increase in mitochondrial biogenesis and oxidative metabolism, augmented muscle capillarization and a remodeling of the neuromuscular junction [193, 194].
Although innervation of the newly implanted tissue is also essential to engineer a functional muscle tissue there is few approaches that could effectively promote nerve ingrowth after transplantation. Some studies described a spontaneous nerve ingrowth from the neighbor tissues into the newly transplanted sites [195, 196], but non-invasive methods to induce nerve ingrowth after newly formed muscle engrafts are still to be investigated. We have recently proposed that magnetic stimulation supports regeneration of injured muscle with activating resident stem cells or supporting integration of newly implanted myoblasts [197, 198]. Exposition of injured limb and co-cultures of muscle cells and neurons to magnetic fields was sufficient to trigger synapses, induce acetylcholine receptors clustering and cause typical muscular metabolic adaptations verified during endurance exercise [197]. Notwithstanding, magnetic stimulation mimicked the effects of exercise inducing PGC-1α up-regulation, induces myogenic cells differentiation and increases nerve fibers and acetylcholine receptor clustering after cell transplantation [198]. New efforts in establishing functional innervation, proper vascular network and the development of a high endurance resistance muscle are going to be the three main pillars supporting future translational studies and bringing myogenic cell transplantation from bench to bedside.
Regeneration of skeletal muscle for SUI is becoming a reality and the cell therapy may soon be available to patients. Tremendous progresses have been made to understand the science behind the natural process of skeletal muscle regeneration that involves primarily satellite cells and their progenitors, MPCs. In addition, these cells are now well-characterized with several markers at different stages of proliferation and differentiation. They are also interacting actively with their environment, which is composed of different types of cells. These neighboring cells have a significant influence on the environment and on stimulating the factors that trigger satellite cells renewal, proliferation and differentiation into myofibers. The process is complicated and involves cocktails of factors and cells. However, the interaction between these parameters is better-understood and applied in research and preclinical studies to ameliorate lack of early vascularization and innervation. In clinical trials, the first results are promising and many patients with SUI were treated successfully. The cell sources are important for a successful skeletal muscle cell therapy but they must be accompanied by a set of tools to ensure the safety and the quality of the process: culture medium, biomaterials, imaging for injection and follow-up. The advances have been made and the solutions are ready, even at the regulatory level. Although, there is not yet a standardized cell therapy for SUI, the solutions and the first results are encouraging. The cell therapy for SUI treatment will be certainly part of the choices that urologists will adopt very soon in hospitals.
The authors would like to thank Mrs. Damina Balmer for her editorial assistance.
The rapid evolution in the field of technologies related to nanomanufacturing and nano-devices based on electrical, optic, magnetic, mechanic, chemical, and biological effects would allow measurements in specific length ranges involved. Moreover, the spectacular development of nanotechnology in recent years generated the development of new devices and smaller components, trends that have created the need to measure them by developing a new nanometrology field. For standard products, measurement and control systems and equipment have been created in hundreds of years, but for nano-metric components, new appropriate measurement systems must to be created quickly. In most cases the physical principle used to measure in the usual nano-production flow from a technical point of view does not correspond with normal measurement systems. Traditional measuring means have proved some technological limits in terms of accuracy because of the physical law constraints [1, 2, 3]. Furthermore, microsensors, transducers, and ultra-accurate machines must be calibrated or verified during production and, afterward, before reception at beneficiary, because it is through them that the measuring unit is transmitted to dedicated users, meaning final producers [4].
Control and measurement techniques in nanotechnologies face specific challenges at the actual incipient stage and form tolerances of the nano-products exceeding actual measurement equipments and standards, and new generation of performant electromechanical systems is required in the field of nanometrics [5, 6]. Thus, innovative devices based on new measurement principles have been used and developed. Industrial production implies increasing manufacturing speeds on the one hand and increasing accuracy of manufacturing on the other. This can be achieved by automating and robotizing both production and production control.
Different industries developed new innovative products or materials involved that currently utilize nanotechnology. The nanoscale analysis of biosystems and of specific materials started years ago (beginning of the twentieth century) when chemistry and physics allowed small-scale characterization (bacteria, fungi studies). Recent development of medicine applications, nano-characteristics of drugs or nano-surgery, has generated advanced progress in engineering building new nanoscale systems and creating new nano-technics [7].
Other areas of emerging technologies include semiconductors and optoelectronic design and production, which increase the progress of information and communication technologies (ICT). More and more positive results engaged new initiatives and contributed to develop nanotechnology applications for structures smaller than 100 nm. Actual growth of semiconductor industry exploded toward nanotechnology boost and industrial demand raised in the last few years, generating unstable economic expansion for electronic devices in term of quality.
New nanotechnologies penetrated globally in large areas, from electronics to optical devices and from new materials to biological systems, considering upgrade of specific and customized makers offering optimal and functional parameters of the new products. This is further relevant conceiving nano-systems based on optical, electronical, mechanical, and biological nano-devices [8].
In Romania and widely, we only find significant research and innovation projects for nano-systems and nanometrology reaching the TLR 3–4 level, stage that needs upscaling to TLR 6–8. Further, industrial nano-production needs calibrated applications and metrological infrastructure at nano-dimensions to be scaled up from laboratory stage to industrial systems, which follow the quality parameters of the production flow for every relevant process [9].
Evolving toward precise production, innovations are required for efficient production structure of control systems by designing them for accreditation; thus, some procedures ask for specific parameters that are necessary to be checked.
Nanoscale dimensional accuracy covers a narrow range of tolerances. Industrial systems in nano-production can’t detect smaller deviations beyond the normal tolerances, and that may have unpleasant effects by damaging the production systems. Any nano-production system requires rigorous control and verification procedure based on dimensional checking; the field of nanometrology is not developed accordingly [10].
Research and innovation in nanometrology expand the number of interested scholars, who will be supporting widely new sustainable production of nano-devices, nano-systems, and nano-materials.
Industrial processes, from medical devices to aeronautics, involve a structure where process accuracy and product quality are supervised by a system of characteristic control for every landmark product, ensuring interchangeability of product parts and the functional parameters of the product [11].
Only a few organizations have integrated this kind of research; most applications are limited at laboratory findings. The main barrier of using nanotechnology control at large industrial scale is the lack of specific infrastructure; for that reason this study proposes some solutions (Figure 1) [8, 9, 10].
Nano-electronics devices.
The equipment for nanometrology further presented is based on the experience of more than 30 years in research and didactic activity of the main author in the field of measuring devices and dimensional control systems. Activity in the field began with the design of control systems and devices from precision mechanics, with laser measuring and controlling equipment (laser probe heads, laser beam-scanning measuring systems, 3D cordless measuring machines, laser head, laser camshaft measuring equipment, laser calibration of coordinate measuring machines, and precision tool machines) [12].
The advantages of studying and realizing these systems are the basis for the next research and innovative solutions for nano-industries in terms of quality and precise manufacturing. The disadvantages are that systems and benchmarks to be verified in nanotechnological production are not palpable and in most cases are easily deformable and only distinguishable by a microscope. The transition from metrology to nanometrology required a new approach. Touch contact systems can no longer be used; the appropriate optical measurement principle—video inspection, laser scanning, and atomic force microscope (AFM) testing—must be approached.
The equipment is designed and developed by a multidisciplinary team from INCDMTM (National Institute for Research Development for Mechatronics and Measurement Technique) in Bucharest. The equipment is mainly driven by the need to control the production flow of a recognized mobile phone company based in Romania. Meanwhile, the mobile phone company ended its tax-free period and relocated its production from Romania to another country.
The chapter is structured according to primarily an introduction which highlighted the state of the art of this theme and secondly to describing the main parts of the equipment structure (experimental model). This includes Subchapter 2.1 that shows the optoelectronic control system including the charge-coupled device (CCD) camera, with examples of controllable nano-sensors; Subchapter 2.2 presents briefly the following control station with the laser control system; and then in Subchapter 2.3, the control station with the atomic force microscope (AFM) is shown, followed by a brief conclusion and direction for future research.
The experimental model presented in this paper for an innovative control and calibration equipment is built based on rotary feeding systems including table supports which are installed very precisely holding the nano-devices that need to be verified and calibrated. The equipment design allows calibration for a series of electronic nano-devices, bio-nano-devices, nano-materials, nano-sensors, or other nano-devices (Figure 2).
Variety of Nano-devices necessary to be verified.
The very thin nano-device calibration requires dedicated operational procedure for handling, and it is using support parts manipulated by a precision linear displacement system. These systems transfer the nano-devices by specialized automatic options (robot) to different precision measurement systems—optoelectronic, laser, or AFM—for calibration [3].
As shown in Figure 3, the equipment comprises a rotary feeding system, on top of which are placed eight support tables. On each support table, there is a specific plate support where nano-devices are introduced to follow the calibration procedure.
Optoelectronic measuring and calibration system assisted by laser and AFM control.
Experimental equipment includes mechanical, optical, and optoelectronic sub-ensembles, the optoelectronic measurement sub-ensembles, and the algorithms related to (real time) measurement system data acquisition, data processing, and measurement protocol presentation.
Control equipment (Figure 4) uses a rotary handling system including a feeding robot manipulator, a precision linear moving system, an optical measuring system, a laser measuring system, and a measuring system equipped with an atomic force microscope (AFM) [3].
The experimental equipment model.
The technical features of this experimental model ensure the following precision by:
Displacement accuracy of the ultra-accurate-controlled linear positioning systems, 0.2 nm
Laser measurement resolution, 1 nm
AFM characterization resolution, less than 0.5 nm
Optoelectronic measurement resolution, 10 nm
Calibration procedure secures the nano-device optimal positioning in the support dedicated plate, which is precisely fixed on the support table from the rotary feeding system by computer coordination and transfer manipulator, which allows adjustments of the table during the precision displacement. For measuring operations with an AFM, a special feeding robot is used in order to keep accurate calibration characteristics. Dedicated computer programming procedure of the calibration system decides if the device is accepted (qualifying as good) continuing the production flow or is rejected (is not respecting the quality required) to scrap boxes (Figure 5).
Optoelectronic control.
The nanotechnological process can be adjusted using this equipment by programming automatic calibration for one, two, or three posts from eight available table supports [13]. The control software is versatile ordering automatic calibration process or manually controlled by a computer system or using touch screen applications.
The equipment developed in research institute INCDMTM is equipped to perform the flow control by means of three specialized systems:
Optoelectronic control (microscope with CCD camera)
Laser control
AFM control
In this chapter the integrated control processes for nano-production flow using these three dedicated systems are presented summarily.
This testing and controlling method permits to check up the quality and cohesion of different nano-devices: semiconductor devices (SMD discrete components), microelectronic circuits, micromachined circuits, printed microcircuits, microsensors, and transducers. The optoelectronic control method using CCD camera may be adopted for finding defects from handling, assembling, or encapsulating all types of devices listed above [3] (Figure 6).
Integrated circuit.
The equipment used in this control process must be able to demonstrate the quality conditions of the devices mentioned in accordance with the requirements envisaged in the product design.
Equipment should include optics (optical microscope) with a magnification range of 1.5–20 X with a view area accessible and large enough for determination of details. The control procedure sets up the devices that will be examined by producers at established magnifications ranging from 1.5 to 20 X. Measurements of dimensions (length/width/diameter) will be made using the order of the same range of magnification that provide good accuracy of measurements.
The dimensional measurements with optoelectronic microscope are ranked (width, length routes, or contacts) in the range of 10–2000 μm, and measurement resolution is 10 nm. The system offers rigorous linear movement of the sample nano-device based on two perpendicular directions at a distance of at least 5 mm (matching the test plan). In this case, measuring resolution should be less than 100 nm (Figure 7).
Microprocessed circuits.
Applications that require the optical control are verification of integrated circuits, verification of printed microcircuits, and verification of microsensors based on amorphous magnetic materials.
Some examples of the optoelectronic control applications in microelectronic circuits, micromachined circuits, printed microcircuits, and microsensors are shown (Figures 8–13).
Microelectronic circuits.
Micro-imprinted circuits.
Microcircuits.
Microcircuit.
Cable routes and metal-plated holes.
Inductive sensor.
Verification of integrated circuit (Figures 8 and 9) procedure includes:
Verification of routes and establishing dimensional variations from the geometry of the proposed design by comparing with a theoretical form
Verification of junctions and contacts
Verification of profiles
Verification of printed microcircuit (Figures 10 and 11) procedure includes:
Controlling the framing of deviations from the theoretical geometric shape of a circuit within the prescribed limit
Control of circuit breaks
Control of the geometric shape of the circuit
Control of the presence and correct positioning of the components on the circuit
Dimensional component control
Verification of microsensors based on amorphous magnetic material (Figures 12 and 13) procedure includes:
Dimensional sensor control.
Control of each sensor component.
Control the correct positioning for each sensor on the circuit.
Control the alignment of each sensor in the circuit.
Laser measurement technologies gradually developed using multiple measurement principles that allow a large control flexibility and applicability for measurement and checking procedures.
Laser telemetry measurement principle offers a great variability of distance measuring systems up to kilometer lengths. The INCDMTM center developed applications to measure distance by telemetry satellites during the formation flying useful to maintain and adjust flying positioning. This application allows monitoring of distance length between satellites, and it controls trajectory of each satellite for keeping formation flying.
Interferometry principle is used for measurement covering distances of 80–120 meters and allows high resolution up to 0.01 nm. With a large experience in the development of checking and measurement applications for sensors, transducers, coordinate measuring machines, and precise CNC machines, we proposed to use the interferometry principle for nanotechnology processes where very precise displacements in a network system can be supervised with specific sensors. Laser triangulation is an accurate measurement principle with resolution of 1 nm. This method uses measurement referential to a point for distance and object presence determinations or referential to a line covering 3D forms and a profile dimension.
The new equipment designed for very precise measurement within time checking methods applies triangulation principle. Nevertheless our institute developed measuring systems using triangulation method 30 years ago [1]; in this case to assemble this measuring equipment on the nano-production flow, we acquired some measuring systems from a specialized company.
The purpose of using this method of control is to check the quality conditions of the semiconductor devices (discrete component-type SMD) of microsensors and transducers (e.g., control surfaces, movement control, control distance/size, position control, etc.).
The equipment used in this control must be able to demonstrate the quality conditions of the devices mentioned in accordance with the requirements envisaged in the design. It should include laser equipment and devices enabling precision movements on three axes (nano-positioning stage).
The measuring principle is the method of triangulation, having a measuring range of 5 mm, measurement resolution of 1 nm, and laser measurement resolution of 1 nm.
The value of the dimensions (width/length/height of routes, etc.) that can be checked is in the range 1–2000 μm. The system allows linear movement of the sample in three directions perpendicular to distances of at least 5 mm with nanometer precision. The precise positioning table is fixed in the laser calibration position as shown in Figure 14.
Calibration with laser.
One of the applications appropriate for using laser-based measuring method is verification of integrated circuits, procedure that includes:
Verification of routes and dimensional variations of the geometry identified to the proposed design by comparing with a theoretical form
Verification of junctions and contacts
Verification of profiles
Some examples of electronic microcircuits where laser control is applicable are shown in Figures 15–17. First, one control application defined by triangulation method for measuring and verification of the profile, positioning, and present splice of a pin in the integrated circuit is presented in Figure 15.
Verification of the profile of pins for an integrated circuit.
Verification of the profile of microcircuits (a) and integrated circuits (b).
Gripper clamps up the nano-device support.
In microcircuit manufacturing, one important issue raised by specialists is the presence and correct checking position of each specific component to ensure the designed function of integrated circuits. This checking is presented in Figure 16(a) using a Keyence scanner. Continuous trends of minimizing the characteristic dimensions in integrated circuits and the rapid multiplication of functions determined for the same products lead to specialized very fine and narrow circuits’ paths. Each circuit’s path must to be produced respecting some rigorous requirements: minimum dimensions, distance between two of the closed paths, and the transversal profile of each path line. If the checking of circuit’s form and the correspondence with theoretical design of the final product is realized with optoelectronic methods using video inspection, the verification of integrated circuit parameters is made by laser triangulation as shown in Figure 16(b).
One of the problematic issues in the nano-production line control is the automatic maneuver of nano-devices. To protect nano-devices (microcircuits) during checking operations, there are specific item supports used with automatic precise displacement. Therefore, considering the nano-device control procedures, all parameters settled for measurement can be easily provided in each control point of the new equipment (optical, laser, and especially for atomic force microscope, AFM, characterization).
The purpose of using this AFM control method for nano-device testing and inspection plays an important role, and it is appropriate to check and to keep right conditions of integrity and quality of porous alumina membranes (alumina template) having pore sizes included in the nanometer range.
This control method can be used for inspecting defects that may result from the production (manufacturing industry), handling, or assembly of alumina membranes [9]. Control equipment used must be able to demonstrate the quality conditions of the porous alumina membranes in accordance with the requirements envisaged by product theoretical design. Control equipment is endowed with specialized systems that include an AFM.
The method of verification, control, and calibration includes the following procedure characteristics:
The device must provide noncontact imaging solutions for nanoscale metrology.
The scanning range on XY (sample plan) must be at least 100 × 100 μm.
The scanning range on Z must be at least 25 μm.
The values of dimensions (width/length, diameter pores, etc.) that can be checked are in the range of 1–500 nm.
The system allows motorized sample stage in three directions, at a distance of at least 5 mm.
The measuring resolution must be higher than 0.5 nm.
Applicable for AFM control are porous alumina membranes used for obtaining nanowires via the electrode position process, and the procedure includes:
Verification of the dimensional pore width and of the geometry of the proposed design, compared with theoretical form.
Verification of membrane integrity.
Verification of profiles.
Checking and control method using AFM is described summarily as follows: nano-devices are positioned on the support plate which is useful for automatic maneuver. Maneuver operations are driven by a robot that has a clapping system for interoperation displacements of support plates (Figure 17).
Before automatic operation offsets, it is required to set up the measuring head of AFM, which is equipped with a special support fixed on the adjustment unit of this head. The special support must be provided with guidance systems for support plate corresponding to each nano-device that must be calibrated. Adaptation of AFM measuring head position is settled following two rectangular directions using two fine-pitch screws that allow micron precise positioning of the measuring head referential to laser beam. Setting up of detection systems is performed by using control software program.
Automatic feeding of support plates with nano-devices is completed by a precise robot using a special gripper with fine claw clamps that hold and fix the support plates with nano-device in specific hole. Gripper form allows maneuver and fixing of nano-device support compatible with the guiding system of the special support from AFM measuring head.
One important issue regarding AFM operation is the laser beam alignment into the cantilever. For nano-device precise positioning for calibration procedure, a universal measuring head was selected. The laser beam alignment is realized by joist displacement in cantilever in relation to the beam spot.
The gripper clamps up the support table with the calibration nano-device, and it is built to introduce the nano-device fixed on its support plate ready to be verified directly in the AFM socket without protection cap removal (Figure 18). This automatic process using AFM control admits time-saving and more productivity.
Robot lifting nano-device related with AFM positioning socket.
The robot lifts the support with the nano-device that must be calibrated to the height of the positioning socket of the AFM and introduces that support in the right position (Figures 18 and 19).
Robot positioning nano-device support plate in the AFM socket.
The robot clamps off the gripper and takes down the support with the device that needs to be calibrated, and the AFM catches and holds the nano-device in the calibration position (Figure 20).
Robotic performance of AFM calibration.
Control and checking technology defines if the verification is done in each checking position or only in a few checking positions and ensures the monitoring of settled characteristics important to be verified in every checking position. After every finalized checking operation, the equipment decides if the nano-device is within the tolerance limits and if it is accepted or not. If a specific characteristic of every nano-device is not corresponding within the settled limits of the technology that is designated by the measurement program, the feeding robot receives the command REBUT in every checking position, and the nano-device is eliminated from the production flow [13]. If the nano-device is accepted according to settled limits for each checking position, the robot receives the command GOOD, and the nano-device is introduced ensuing further into production flow.
Some relevant pictures present examples of AFM control applicability to porous alumina membranes where pore diameters are in the range of nanometers (Figures 21–23).
Porous alumina membranes with pore diameters at nanoscale (SEM image) (a) top view and (b) lateral view.
Nanowires obtained through the process of nano-disposition in porous alumina membranes (SEM images).
Nanowires in the porous alumina membrane (AFM image).
The images from Figures 21–23 are achieved in the National Institute of Research and Development for Technical Physics, Iasi, Romania, during the collaborative research using scanning electron microscope (SEM) and AFM. These applications are demonstrative for AFM characterization and are dedicated for very precise control and checking processes in the nano-production flow.
The experimental model permits optical, laser, and AFM microscopic verifications of realized nano-devices in order to correct possible production errors [3, 6, 12, 13]; thus, it allows nano-production calibration and automatic selection of rebuttal during flow processes for dedicated dimensional control in range from less than 1 nm up to micrometers or millimeters.
Future research will aim at the development of detailed technologies for various applications in nano-device production field that need to be calibrated covering all ranges of electronic nano-devices, optical nano-devices, biological nano-devices, nano-materials, and nano-sensors.
To evolve from laboratory stage to nanotechnology production lines, more research and innovations may allow over passing the actual barriers:
Traditional measurement techniques used for normal dimensional characterization cannot be applied to nano-structures.
Special rules and standards must be introduced for nano-structures and nano-material characterization reducing errors in inspection and quality checking procedures.
More innovative equipments must be projected in order to solve the mentioned issues.
Different specific studies for new equipments for control production regarding nano-structure proprieties should promote reproducible production of nano-structures and nano-materials.
Nanometrology opens opportunity creation of international standards and equipments for calibration of the products and equipments used in industrial production and offers more chances of new scientific discoveries regarding innovative commercial products.
The future development of nanotechnology cannot be achieved without progress in ensuring a well-controlled, stable production carrying dimensional control and in terms of other quality characteristics. This depends both on the strategy of each area of development and especially on the joint development of the nanotechnology field. First, research should be coordinated and developed in collaboration with companies, and secondly research for standardization in the field of nanometrology must be promoted by government programs. Efforts need to be united between those with common concerns for the progress of the nanotechnologies in precise industry.
For unitary development and interchangeable products, rules and standards need to be created at European and international status both for the acceptance of production and for systematization of products and components at the nanoscale. For large-scale production of nanotechnology products, equipments must be developed for both industrial production and production control. In order to ensure stable production, international rules must be developed and immerged for calibration of production flow and for calibration of control equipment production. Another issue that needs to be considered is that of environmental production conditions. We need to rethink environmental standards for this type of production. The old classification and standardization of clean rooms no longer correspond, and it is necessary to improve the clean room technical standards and add specific parameters. At the atomic force microscope (AFM), the measured parameter value is drastically influenced by its position relative to the air circulation system, noise, and vibration not only of temperature and humidity.
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She performed research in perioperative autotransfusion and obtained the degree of PhD in 1993 publishing Peri-operative autotransfusion by means of a blood cell separator.\nBlood transfusion had her special interest being the president of the Haemovigilance Chamber TRIP and performing several tasks in local and national blood bank and anticoagulant-blood transfusion guidelines committees. Currently, she is working as an associate professor and up till recently was the dean at the Albert Schweitzer Hospital Dordrecht. She performed (inter)national tasks as vice-president of the Concilium Anaesthesia and related committees. \nShe performed research in several fields, with over 100 publications in (inter)national journals and numerous papers on scientific conferences. \nShe received several awards and is a member of Honour of the Dutch Society of Anaesthesia.",institutionString:null,institution:{name:"Albert Schweitzer Hospital",country:{name:"Gabon"}}},{id:"83089",title:"Prof.",name:"Aaron",middleName:null,surname:"Ojule",slug:"aaron-ojule",fullName:"Aaron Ojule",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Port Harcourt",country:{name:"Nigeria"}}},{id:"295748",title:"Mr.",name:"Abayomi",middleName:null,surname:"Modupe",slug:"abayomi-modupe",fullName:"Abayomi Modupe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/no_image.jpg",biography:null,institutionString:null,institution:{name:"Landmark University",country:{name:"Nigeria"}}},{id:"94191",title:"Prof.",name:"Abbas",middleName:null,surname:"Moustafa",slug:"abbas-moustafa",fullName:"Abbas Moustafa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94191/images/96_n.jpg",biography:"Prof. Moustafa got his doctoral degree in earthquake engineering and structural safety from Indian Institute of Science in 2002. He is currently an associate professor at Department of Civil Engineering, Minia University, Egypt and the chairman of Department of Civil Engineering, High Institute of Engineering and Technology, Giza, Egypt. He is also a consultant engineer and head of structural group at Hamza Associates, Giza, Egypt. Dr. Moustafa was a senior research associate at Vanderbilt University and a JSPS fellow at Kyoto and Nagasaki Universities. He has more than 40 research papers published in international journals and conferences. He acts as an editorial board member and a reviewer for several regional and international journals. His research interest includes earthquake engineering, seismic design, nonlinear dynamics, random vibration, structural reliability, structural health monitoring and uncertainty modeling.",institutionString:null,institution:{name:"Minia University",country:{name:"Egypt"}}},{id:"84562",title:"Dr.",name:"Abbyssinia",middleName:null,surname:"Mushunje",slug:"abbyssinia-mushunje",fullName:"Abbyssinia Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Fort Hare",country:{name:"South Africa"}}},{id:"202206",title:"Associate Prof.",name:"Abd Elmoniem",middleName:"Ahmed",surname:"Elzain",slug:"abd-elmoniem-elzain",fullName:"Abd Elmoniem Elzain",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Kassala University",country:{name:"Sudan"}}},{id:"98127",title:"Dr.",name:"Abdallah",middleName:null,surname:"Handoura",slug:"abdallah-handoura",fullName:"Abdallah Handoura",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Supérieure des Télécommunications",country:{name:"Morocco"}}},{id:"91404",title:"Prof.",name:"Abdecharif",middleName:null,surname:"Boumaza",slug:"abdecharif-boumaza",fullName:"Abdecharif Boumaza",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Abbès Laghrour University of Khenchela",country:{name:"Algeria"}}},{id:"105795",title:"Prof.",name:"Abdel Ghani",middleName:null,surname:"Aissaoui",slug:"abdel-ghani-aissaoui",fullName:"Abdel Ghani Aissaoui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/105795/images/system/105795.jpeg",biography:"Abdel Ghani AISSAOUI is a Full Professor of electrical engineering at University of Bechar (ALGERIA). He was born in 1969 in Naama, Algeria. He received his BS degree in 1993, the MS degree in 1997, the PhD degree in 2007 from the Electrical Engineering Institute of Djilali Liabes University of Sidi Bel Abbes (ALGERIA). He is an active member of IRECOM (Interaction Réseaux Electriques - COnvertisseurs Machines) Laboratory and IEEE senior member. He is an editor member for many international journals (IJET, RSE, MER, IJECE, etc.), he serves as a reviewer in international journals (IJAC, ECPS, COMPEL, etc.). He serves as member in technical committee (TPC) and reviewer in international conferences (CHUSER 2011, SHUSER 2012, PECON 2012, SAI 2013, SCSE2013, SDM2014, SEB2014, PEMC2014, PEAM2014, SEB (2014, 2015), ICRERA (2015, 2016, 2017, 2018,-2019), etc.). His current research interest includes power electronics, control of electrical machines, artificial intelligence and Renewable energies.",institutionString:"University of Béchar",institution:{name:"University of Béchar",country:{name:"Algeria"}}},{id:"99749",title:"Dr.",name:"Abdel Hafid",middleName:null,surname:"Essadki",slug:"abdel-hafid-essadki",fullName:"Abdel Hafid Essadki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"École Nationale Supérieure de Technologie",country:{name:"Algeria"}}},{id:"101208",title:"Prof.",name:"Abdel Karim",middleName:"Mohamad",surname:"El Hemaly",slug:"abdel-karim-el-hemaly",fullName:"Abdel Karim El Hemaly",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/101208/images/733_n.jpg",biography:"OBGYN.net Editorial Advisor Urogynecology.\nAbdel Karim M. A. El-Hemaly, MRCOG, FRCS � Egypt.\n \nAbdel Karim M. A. El-Hemaly\nProfessor OB/GYN & Urogynecology\nFaculty of medicine, Al-Azhar University \nPersonal Information: \nMarried with two children\nWife: Professor Laila A. Moussa MD.\nSons: Mohamad A. M. El-Hemaly Jr. MD. Died March 25-2007\nMostafa A. M. El-Hemaly, Computer Scientist working at Microsoft Seatle, USA. \nQualifications: \n1.\tM.B.-Bch Cairo Univ. June 1963. \n2.\tDiploma Ob./Gyn. Cairo Univ. April 1966. \n3.\tDiploma Surgery Cairo Univ. Oct. 1966. \n4.\tMRCOG London Feb. 1975. \n5.\tF.R.C.S. Glasgow June 1976. \n6.\tPopulation Study Johns Hopkins 1981. \n7.\tGyn. Oncology Johns Hopkins 1983. \n8.\tAdvanced Laparoscopic Surgery, with Prof. Paulson, Alexandria, Virginia USA 1993. \nSocieties & Associations: \n1.\t Member of the Royal College of Ob./Gyn. London. \n2.\tFellow of the Royal College of Surgeons Glasgow UK. \n3.\tMember of the advisory board on urogyn. FIGO. \n4.\tMember of the New York Academy of Sciences. \n5.\tMember of the American Association for the Advancement of Science. \n6.\tFeatured in �Who is Who in the World� from the 16th edition to the 20th edition. \n7.\tFeatured in �Who is Who in Science and Engineering� in the 7th edition. \n8.\tMember of the Egyptian Fertility & Sterility Society. \n9.\tMember of the Egyptian Society of Ob./Gyn. \n10.\tMember of the Egyptian Society of Urogyn. \n\nScientific Publications & Communications:\n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Asim Kurjak, Ahmad G. Serour, Laila A. S. Mousa, Amr M. Zaied, Khalid Z. El Sheikha. \nImaging the Internal Urethral Sphincter and the Vagina in Normal Women and Women Suffering from Stress Urinary Incontinence and Vaginal Prolapse. Gynaecologia Et Perinatologia, Vol18, No 4; 169-286 October-December 2009.\n2- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nFecal Incontinence, A Novel Concept: The Role of the internal Anal sphincter (IAS) in defecation and fecal incontinence. Gynaecologia Et Perinatologia, Vol19, No 2; 79-85 April -June 2010.\n3- Abdel Karim M. El Hemaly*, Laila A. S. Mousa Ibrahim M. Kandil, Fatma S. El Sokkary, Ahmad G. Serour, Hossam Hussein.\nSurgical Treatment of Stress Urinary Incontinence, Fecal Incontinence and Vaginal Prolapse By A Novel Operation \n"Urethro-Ano-Vaginoplasty"\n Gynaecologia Et Perinatologia, Vol19, No 3; 129-188 July-September 2010.\n4- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n5- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n6- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n7-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n8-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n9-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n10-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n11-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n12- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n13-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n14- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Mohamad A. Rizk and Mohamad A.K.M.El Hemaly.\n Urethro-plasty, a Novel Operation based on a New Concept, for the Treatment of Stress Urinary Incontinence, S.U.I., Detrusor Instability, D.I., and Mixed-type of Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/urethro-plasty_01\n\n15-Ibrahim M. Kandil, Abdel Karim M. El Hemaly, Mohamad M. Radwan: Ultrasonic Assessment of the Internal Urethral Sphincter in Stress Urinary Incontinence. The Internet Journal of Gynecology and Obstetrics. 2003. Volume 2 Number 1. \n\n\n16-Abdel Karim M. El Hemaly. Nocturnal Enureses: A Novel Concept on its pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecolgy/?page=articles/nocturnal_enuresis\n\n17- Abdel Karim M. El Hemaly. Nocturnal Enureses: An Update on the pathogenesis and Treatment.\nhttp://www.obgyn.net/urogynecology/?page=/ENHLIDH/PUBD/FEATURES/\nPresentations/ Nocturnal_Enuresis/nocturnal_enuresis\n\n18-Maternal Mortality in Egypt, a cry for help and attention. The Second International Conference of the African Society of Organization & Gestosis, 1998, 3rd Annual International Conference of Ob/Gyn Department � Sohag Faculty of Medicine University. Feb. 11-13. Luxor, Egypt. \n19-Postmenopausal Osteprosis. The 2nd annual conference of Health Insurance Organization on Family Planning and its role in primary health care. Zagaziz, Egypt, February 26-27, 1997, Center of Complementary Services for Maternity and childhood care. \n20-Laparoscopic Assisted vaginal hysterectomy. 10th International Annual Congress Modern Trends in Reproductive Techniques 23-24 March 1995. Alexandria, Egypt. \n21-Immunological Studies in Pre-eclamptic Toxaemia. Proceedings of 10th Annual Ain Shams Medical Congress. Cairo, Egypt, March 6-10, 1987. \n22-Socio-demographic factorse affecting acceptability of the long-acting contraceptive injections in a rural Egyptian community. Journal of Biosocial Science 29:305, 1987. \n23-Plasma fibronectin levels hypertension during pregnancy. The Journal of the Egypt. Soc. of Ob./Gyn. 13:1, 17-21, Jan. 1987. \n24-Effect of smoking on pregnancy. Journal of Egypt. Soc. of Ob./Gyn. 12:3, 111-121, Sept 1986. \n25-Socio-demographic aspects of nausea and vomiting in early pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 35-42, Sept. 1986. \n26-Effect of intrapartum oxygen inhalation on maternofetal blood gases and pH. Journal of the Egypt. Soc. of Ob./Gyn. 12:3, 57-64, Sept. 1986. \n27-The effect of severe pre-eclampsia on serum transaminases. The Egypt. J. Med. Sci. 7(2): 479-485, 1986. \n28-A study of placental immunoreceptors in pre-eclampsia. The Egypt. J. Med. Sci. 7(2): 211-216, 1986. \n29-Serum human placental lactogen (hpl) in normal, toxaemic and diabetic pregnant women, during pregnancy and its relation to the outcome of pregnancy. Journal of the Egypt. Soc. of Ob./Gyn. 12:2, 11-23, May 1986. \n30-Pregnancy specific B1 Glycoprotein and free estriol in the serum of normal, toxaemic and diabetic pregnant women during pregnancy and after delivery. Journal of the Egypt. Soc. of Ob./Gyn. 12:1, 63-70, Jan. 1986. Also was accepted and presented at Xith World Congress of Gynecology and Obstetrics, Berlin (West), September 15-20, 1985. \n31-Pregnancy and labor in women over the age of forty years. Accepted and presented at Al-Azhar International Medical Conference, Cairo 28-31 Dec. 1985. \n32-Effect of Copper T intra-uterine device on cervico-vaginal flora. Int. J. Gynaecol. Obstet. 23:2, 153-156, April 1985. \n33-Factors affecting the occurrence of post-Caesarean section febrile morbidity. Population Sciences, 6, 139-149, 1985. \n34-Pre-eclamptic toxaemia and its relation to H.L.A. system. Population Sciences, 6, 131-139, 1985. \n35-The menstrual pattern and occurrence of pregnancy one year after discontinuation of Depo-medroxy progesterone acetate as a postpartum contraceptive. Population Sciences, 6, 105-111, 1985. \n36-The menstrual pattern and side effects of Depo-medroxy progesterone acetate as postpartum contraceptive. Population Sciences, 6, 97-105, 1985. \n37-Actinomyces in the vaginas of women with and without intrauterine contraceptive devices. Population Sciences, 6, 77-85, 1985. \n38-Comparative efficacy of ibuprofen and etamsylate in the treatment of I.U.D. menorrhagia. Population Sciences, 6, 63-77, 1985. \n39-Changes in cervical mucus copper and zinc in women using I.U.D.�s. Population Sciences, 6, 35-41, 1985. \n40-Histochemical study of the endometrium of infertile women. Egypt. J. Histol. 8(1) 63-66, 1985. \n41-Genital flora in pre- and post-menopausal women. Egypt. J. Med. Sci. 4(2), 165-172, 1983. \n42-Evaluation of the vaginal rugae and thickness in 8 different groups. Journal of the Egypt. Soc. of Ob./Gyn. 9:2, 101-114, May 1983. \n43-The effect of menopausal status and conjugated oestrogen therapy on serum cholesterol, triglycerides and electrophoretic lipoprotein patterns. Al-Azhar Medical Journal, 12:2, 113-119, April 1983. \n44-Laparoscopic ventrosuspension: A New Technique. Int. J. Gynaecol. Obstet., 20, 129-31, 1982. \n45-The laparoscope: A useful diagnostic tool in general surgery. Al-Azhar Medical Journal, 11:4, 397-401, Oct. 1982. \n46-The value of the laparoscope in the diagnosis of polycystic ovary. Al-Azhar Medical Journal, 11:2, 153-159, April 1982. \n47-An anaesthetic approach to the management of eclampsia. Ain Shams Medical Journal, accepted for publication 1981. \n48-Laparoscopy on patients with previous lower abdominal surgery. Fertility management edited by E. Osman and M. Wahba 1981. \n49-Heart diseases with pregnancy. Population Sciences, 11, 121-130, 1981. \n50-A study of the biosocial factors affecting perinatal mortality in an Egyptian maternity hospital. Population Sciences, 6, 71-90, 1981. \n51-Pregnancy Wastage. Journal of the Egypt. Soc. of Ob./Gyn. 11:3, 57-67, Sept. 1980. \n52-Analysis of maternal deaths in Egyptian maternity hospitals. Population Sciences, 1, 59-65, 1979. \nArticles published on OBGYN.net: \n1- Abdel Karim M. El Hemaly*, Ibrahim M. Kandil, Laila A. S. Mousa and Mohamad A.K.M.El Hemaly.\nUrethro-vaginoplasty, an innovated operation for the treatment of: Stress Urinary Incontinence (SUI), Detursor Overactivity (DO), Mixed Urinary Incontinence and Anterior Vaginal Wall Descent. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/ urethro-vaginoplasty_01\n\n2- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamed M. Radwan.\n Urethro-raphy a new technique for surgical management of Stress Urinary Incontinence.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/\nnew-tech-urethro\n\n3- Abdel Karim M. El Hemaly, Ibrahim M Kandil, Mohamad A. Rizk, Nabil Abdel Maksoud H., Mohamad M. Radwan, Khalid Z. El Shieka, Mohamad A. K. M. El Hemaly, and Ahmad T. El Saban.\nUrethro-raphy The New Operation for the treatment of stress urinary incontinence, SUI, detrusor instability, DI, and mixed-type of urinary incontinence; short and long term results. \nhttp://www.obgyn.net/urogyn/urogyn.asp?page=urogyn/articles/\nurethroraphy-09280\n\n4-Abdel Karim M. El Hemaly, Ibrahim M Kandil, and Bahaa E. El Mohamady. Menopause, and Voiding troubles. \nhttp://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly03/el-hemaly03-ss\n\n5-El Hemaly AKMA, Mousa L.A. Micturition and Urinary\tContinence. Int J Gynecol Obstet 1996; 42: 291-2. \n\n6-Abdel Karim M. El Hemaly.\n Urinary incontinence in gynecology, a review article.\nhttp://www.obgyn.net/urogyn/urogyn.asp?page=/urogyn/articles/abs-urinary_incotinence_gyn_ehemaly \n\n7-El Hemaly AKMA. Nocturnal Enuresis: Pathogenesis and Treatment. \nInt Urogynecol J Pelvic Floor Dysfunct 1998;9: 129-31.\n \n8-El Hemaly AKMA, Mousa L.A.E. Stress Urinary Incontinence, a New Concept. Eur J Obstet Gynecol Reprod Biol 1996; 68: 129-35. \n\n9- El Hemaly AKMA, Kandil I. M. Stress Urinary Incontinence SUI facts and fiction. Is SUI a puzzle?! http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly/el-hemaly-ss\n\n10-Abdel Karim El Hemaly, Nabil Abdel Maksoud, Laila A. Mousa, Ibrahim M. Kandil, Asem Anwar, M.A.K El Hemaly and Bahaa E. El Mohamady. \nEvidence based Facts on the Pathogenesis and Management of SUI. http://www.obgyn.net/displayppt.asp?page=/English/pubs/features/presentations/El-Hemaly02/el-hemaly02-ss\n\n11- Abdel Karim M. El Hemaly*, Ibrahim M. 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