Correspondence to: Riham Mohamed Aly. Department of Basic Dental Science, Oral & Dental Research Division, National Research Centre, 33 El Buhouth St., Dokki, Cairo 12622, Egypt. Email: Riham.aly@hotmail.com.

Corresponding creator.

Received 2020 Jan 3; Accepted 2020 Apr 30; Collection date 2020.

Abstract

Recent analysis reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative methods may someday develop into a remedy for a variety of vexing diseases. In fact, the past few years witnessed, a quite exponential advancement in clinical trials revolving round stem cell-based mostly therapies. Some of these trials resulted in remarkable impact on varied diseases. In this overview, the advances and challenges for the development of stem-cell-primarily based therapies are described, with concentrate on the use of stem cells in dentistry in addition to the advances reached in regenerative remedy modalities in a number of diseases. The constraints of those remedies and ongoing challenges in the sphere are additionally mentioned while shedding gentle on the ethical and regulatory challenges in translating autologous stem cell-primarily based interventions, into protected and effective therapies.

Keywords: Stem cells, therapies, clinical trials, translation

Introduction

Cell-based therapy as a modality of regenerative medicine is taken into account some of the promising disciplines in the fields of fashionable science & medication. Such a complicated expertise gives limitless potentialities for transformative and probably curative therapies for some of humanities most life threatening diseases. Regenerative medication is quickly becoming the following massive factor in well being care with the actual aim of repairing and probably replacing diseased cells, tissues or organs and eventually retrieving regular function. Fortunately, the prospect of regenerative medicine as an alternative to standard drug-based therapies is becoming a tangible reality by the day owing to the vigorous commitment of the analysis communities in finding out the potential purposes across a wide range of diseases like neurodegenerative diseases and diabetes, amongst many others (1).

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative methods may someday develop into a treatment for a variety of vexing diseases (2). In fact, the previous few years witnessed, a reasonably exponential advancement in clinical trials revolving round stem cell-primarily based therapies. Some of these trials resulted in exceptional impression on numerous diseases (3). For instance, a case of Epidermolysis Bullosa manifested signs of pores and skin recovery after remedy with keratinocyte cultures of epidermal stem cells (4). Also, a serious enchancment in eyesight of patients affected by macular degeneration was reported after transplantation of affected person-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina (5).

However, regardless of the elevated quantity of publications reporting profitable cases of stem cell-primarily based therapies, a major variety of clinical trials haven't but acquired full regulatory approvals for validation as stem cell therapies. Thus far, probably the most established stem cell therapy is bone marrow transplants to treat blood and immune system disorders (1,6,7).

On this evaluation, the advances and challenges for the event of stem-cell-primarily based therapies are described, with give attention to the usage of stem cells in dentistry along with the advances reached in regenerative remedy modalities in a number of diseases. The limitations of these remedies and ongoing challenges in the sphere are additionally mentioned whereas shedding mild on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into secure and effective therapies.

Stem cell-primarily based therapies

Stem cell-based mostly therapies are defined as any treatment for a disease or a medical situation that fundamentally involves using any sort of viable human stem cells including embryonic stem cells (ESCs), iPSCs and grownup stem cells for autologous and allogeneic therapies (8). Stem cells provide the perfect solution when there is a need for tissue and organ transplantation via their ability to differentiate into the particular cell varieties which might be required for restore of diseased tissues.

However, the complexity of stem cell-primarily based therapies usually leads researchers to seek for stable, safe and easily accessible stem cells supply that has the potential to differentiate into a number of lineages. Thus, it's of utmost importance to fastidiously choose the kind of stem cells that is appropriate for clinical application (7,9).

Stem cells hierarchy

There are mainly three varieties of stem cells. All three of them share the significant property of self-renewal in addition to a singular ability to differentiate. However, it must be noted that stem cells are usually not homogeneous, however quite exist in a developmental hierarchy (10). Essentially the most primary and undeveloped of stem cells are the totipotent stem cells. These cells are capable of developing into a complete embryo whereas forming the additional-embryonic tissue at the identical time. This unique property is transient and begins with the fertilization of the ovum and ends when the embryo reaches the four to eight cells stage. Following that cells bear subsequent divisions till reaching the blastocyst stage where they lose their totipotency property and assume a pluripotent id the place cells are only capable of differentiating into each embryonic germ layer (ectoderm, mesoderm and endoderm). Cells of this stage are termed "embryonic stem cells" and are obtained by isolation from the inner cell mass of the blastocyst in a process that includes the destruction of the forming embryo. After consecutive divisions, the property of pluripotency is misplaced and the differentiation capability becomes extra lineage restricted the place the cells develop into multipotent which means that they can solely differentiate into restricted kinds of cells related to the tissue of origin. This is the property of "adult stem cells", which helps create a state of homeostasis all through the lifetime of the organism. Adult stem cells are current in a metabolically quiescent state in nearly all specialized tissues of the body, which includes bone marrow and oral and dental tissues amongst many others (11).

Many authors consider grownup stem cells the gold commonplace in stem cell-primarily based therapies (12,13). Adult stem cells demonstrated signs of clinical success especially in hematopoietic transplants (14,15). In distinction to ESCs, grownup stem cells are usually not subjected to controversial views regarding their origin. The fact that ESCs derivation entails destruction of human embryos renders them unacceptable for a major proportion of the population for ethical and religious convictions (16-18).

Turning point in stem cell research

It was in 2006 when Shinya Yamanka achieved a scientific breakthrough in stem cell analysis by succeeding in generating cells which have the same properties and genetic profile of ESCs. This was achieved via the transient over-expression of a cocktail of 4 transcription factors; OCT4, SOX2, KLF4 and MYC in, fully differentiated somatic cells, specifically fibroblasts (19,20). These cells had been called iPSCs and has transformed the field of stem cell research ever since (21). A very powerful characteristic of these cells is their skill to differentiate into any of the germ layers identical to ESCs precluding the ethical debate surrounding their use. The development of iPSCs expertise has created an revolutionary solution to each establish and treat diseases. Since they are often generated from the patient’s own cells, iPSCs thus present a promising potential for the manufacturing of pluripotent derived affected person-matched cells that might be used for autologous transplantation. True these cells symbolize a paradigm shift since they permit researchers to instantly observe and deal with relevant patient cells; nonetheless, various challenges nonetheless must be addressed before iPSCs-derived cells will be utilized in cell therapies. Such challenges embody; the detection and elimination of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that would come up on transplantation (22).

Therapeutic translation of stem cell analysis

With the speedy enhance witnessed in stem cell fundamental analysis over the previous years, the comparatively new analysis discipline "Translational Research" has advanced considerably building up on the outcomes of primary research in order to develop new therapies. The clinical translation pathway begins after acquiring the acceptable regulatory approvals. The importance of translational analysis lies in it’s a role as a filter to make sure that only safe and efficient therapies attain the clinic (23). It bridges the gap from bench to mattress. Currently, some stem cell-based mostly therapies using adult stem cells are clinically accessible and primarily embrace bone marrow transplants of hematopoietic stem cells and pores and skin grafts for extreme burns (23). Up to now, there are more than 3,000 trials involving using grownup stem cells registered in WHO International Clinical Trials Registry. Additionally, initial trials involving the brand new and interesting iPSCs based therapies are also registered. Actually, the first clinical attempt employing iPSCs reported profitable results in treating macular degeneration (24). Given the relative immaturity in the field of cellular therapy, the outcomes of such trials shall facilitate the understanding of the timeframes needed to attain profitable therapies and help in higher understanding of the diseases. However, it is noteworthy that analysis of stem cell-primarily based therapies is just not a straightforward task since transplantation of cells is ectopic and should result in tumor formation and different complications. This accounts for the variations in the outcomes reported from earlier experiences. The next part discusses the printed knowledge of a few of a very powerful clinical trials involving using various kinds of stem cells both in medicine and in dentistry.

Stem cell-based mostly therapy for neurodegenerative diseases

The profitable era of neural cells from stem cells in vitro paved the way for the current stem cell-primarily based clinical trials concentrating on neurodegenerative diseases (25,26). These therapies don't simply target detaining the progression of irrecoverable neuro-degenerative diseases like Parkinson’s, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), but are additionally focused on fully treating such disorders.

Parkinson’s illness (PD)

PD is characterized by a fast lack of midbrain dopaminergic neurons. The primary try for using human ESC cells to deal with PD was through the generation of dopaminergic-like neurons, later human iPSCs was proposed as a substitute to beat ESCs controversies (27). Both cells offered hope for acquiring an endless supply of dopaminergic neurons instead of the previously used fetal brain tissues. Subsequently, protocols that mimicked the development of dopaminergic neurons succeeded in generating dopaminergic neurons similar to that of the midbrain which were able to survive, combine and functionally mature in animal models of PD preclinically (28). Based on the analysis offered by different groups; the "Parkinson’s Global Force" was formed which geared toward guiding researchers to optimize their cell characterization and help promote the clinical progress towards profitable therapy. Recently, In August 2018, Shinya Yamanka initiated the first authorised clinical trial to treat PD utilizing iPSCs. Seven patients suffering from moderate PD were recruited (29). Donor matched allogeneic cells had been used to avoid any genetic affect of the disease. The technique behind the trial concerned the era of dopaminergic progenitors adopted by surgical transplantation into the brains of patients by a special gadget. As well as, immunosuppressant medications have been given to avoid any antagonistic response. Preliminary results thus far revealed the safety of the therapy.

MS

MS is an inflammatory and neurodegenerative autoimmune illness of the central nervous system. Stem cell-based mostly therapies are now exploring the possibility of halting the disease progression and reverse the neural harm. A registered part 1 clinical trial was conducted by the company CelgeneTM in 2014 using placental-derived mesenchymal stem cells (MSCs) infusion to deal with patients affected by MS (30). This trial was performed at 6 centers in the United States and 2 centers in Canada and included sixteen patients. Results demonstrated that cellular infusions have been safe with no indicators of paradoxical aggravation. However, clinical responses from patients indicated that the cellular treatment didn't enhance the MS situation (31). For the final decade immunoablative therapy demonstrated accumulative evidence of inducing lengthy-time period remission and improvement of incapacity caused by MS. This strategy includes the alternative of the diseased immune system through administration of excessive-dose immunosuppressive therapy followed by hematopoietic stem cells infusion (32). However, immunoablation methods demonstrated a number of complications equivalent to infertility and neurological disabilities. Plenty of randomized controlled trials are deliberate to deal with these concerns (32). Currently, new and innovative stem cell-based mostly therapies for MS are only in the preliminary levels, and are primarily based on completely different mechanisms exploring the possibility of replacing broken neuronal tissue with neural cells derived from iPSCs nevertheless, the therapeutic potential of iPSCs continues to be under analysis (33).

ALS

ALS is a neurodegenerative disease that causes degeneration of the motor neurons which ends up in disturbance in muscle efficiency. The primary try to treat ALS was through the transplantation of MSCs in a mouse model. The outcomes of this experiment had been promising and resulted in a lower of the illness manifestations and thus providing proof of principal (34). Based on these outcomes, several deliberate/ongoing clinical trials are on the way in which. These trials primarily assess the security of the proposed concept and have not proved clinical success so far. Notably, whereas pre-clinical research have reported that cells derived from un-diseased people are superior to cells from ALS patients; many of the clinical trials tried have employed autologous transplantation. This data could account for the absence of therapeutic improvement reported (35).

Spinal cord damage

Other neurologic indications for the use of stem cells are spinal cord accidents. Though the transplantation of various types of neural stem cells and oligo-dendrocyte progenitors has led to progress in the axons along with neural connectivity which presents a risk for repair (36), proof of recovered function has yet to be established in stringent clinical trials. Nevertheless, Japan has recently given approval to stem-cell remedy for spinal-cord accidents. This approval was based on clinical trials that are yet to be revealed and entails thirteen patients, who are affected by latest spinal-cord harm. The Japanese group found that injection of stem cells isolated from the patients’ bone marrow aided in regaining some misplaced sensation and mobility. This is the primary stem cell-primarily based therapy focusing on spinal-cord injuries to gain governmental approval to supply to patients (37).

Stem cell-based mostly therapies for ocular diseases

An enormous number of the presently registered clinical trials for stem cell-primarily based therapies goal ocular diseases. This is primarily because of the truth that the attention is an immune privileged site. Most of those trials span numerous international locations including Japan, China, Israel, Korea, UK, and USA and implement allogeneic ESC strains (35,36). Notably, the primary clinical trial to implement the use autologous iPSCs-derived retinal cells was in Japan which adopted the brand new regulatory laws issued in 2014 by Japan’s authorities to regulate regenerative medicine functions. Two patients had been recruited on this trial, the primary one received remedy for macular degeneration using iPSCs-generated retinal cell sheet (37). After 1 year of comply with-up, there were no indicators of severe complications together with abnormal proliferation and systemic malignancy. Moreover, there were no indicators of rejection of the transplanted retinal epithelial sheet within the second year comply with-up. Most importantly, the indicators of corrected visible acuity of the handled eye have been reported. These outcomes have been enough to conclude that iPSCs-primarily based autologous transplantation was protected and possible (38). It is worthy to say that the second affected person was withdrawn from the study as a consequence of detectable genetic variations the patient’s iPSCs strains which was not initially present in the patient’s authentic fibroblasts. Such alterations may jeopardize the general security of the remedy. The truth that this choice was taken, despite the fact that the performed safety assays did not exhibit tumorgenicity within the iPSCs-derived retinal pigment epithelium (RPE) cells, indicates that researchers in the sector of iPSCs have full awareness of the importance of security points (39).

Stem cell-based mostly therapies for remedy of diabetes

Pancreatic beta cells are destructed in sort 1 diabetes mellitus, because of disorders within the immune system while in type 2 insulin insufficiency is caused by failure of the beta-cell to usually produce insulin. In both cases the affected cell is the beta cell, and because the pancreas doesn't efficiently regenerate islets from endogenous grownup stem cells, different cell sources had been tested (38). Pluripotent stem cells (PSCs) are thought of the cells of selection for beta cell substitute strategies (39). Currently, there are a few business-sponsored clinical trials which can be registered concentrating on beta cell substitute using ESCs. These trials revolve across the engraftment of insulin-producing beta cells in an encapsulating system subcutaneously to protect the cells from autoimmunity in patients with kind 1 diabetes (40). The company ViaCyteTM in California not too long ago initiated a part I/II trial (NCT02239354) in 2014 in collaboration with Harvard University. This trial includes 40 patients and employs two subcutaneous capsules of insulin producing beta cells generated from ESCs. The results shall be attention-grabbing as a result of the benefit of monitoring and restoration of the transplanted cells. The preclinical research previous this trial demonstrated successful glycemic correction and the units had been successfully retrieved after 174 days and contained viable insulin-producing cells (41).

Stem cells in dentistry

Stem cells have been successfully isolated from human teeth and had been studied to test their capability to regenerate dental structures and periodontal tissues. MSCs had been reported to be efficiently isolated from dental tissues like dental pulp of everlasting and deciduous teeth, periodontal ligament, apical papilla and dental follicle (42-44). These cells have been described as a superb cell supply owing to their ease of accessibility, their capability to differentiate into osteoblasts and odontoblasts and lack of moral controversies (45). Moreover, dental stem cells demonstrated superior skills in immunomodulation properties both by way of cell to cell interaction or via a paracrine impact (46). Stem cells of non-dental origin had been also prompt for dental tissue and bone regeneration. Different approaches have been investigated for achieving dental and periodontal regeneration (47); however, assessments of stem cells after transplantation nonetheless require intensive studying. Clinical trials have only recently begun and their outcomes are but to be absolutely evaluated. However, by rigorously making use of the knowledge acquired from the intensive primary research in dental and periodontal regeneration, stem cell-primarily based dental and periodontal regeneration might quickly be a readily out there remedy. Thus far, there are more than 6,000 clinical trials involving the use of with stem cells, nevertheless solely a complete of 44 registered clinical trials address oral diseases worldwide (48). Stem cell-based clinical trials with reported outcomes focusing on the remedy of oral illness are discussed under.

Dental pulp regeneration

The first human clinical examine using autologous dental pulp stem cells (DPSCs) for full pulp regeneration was reported by Nakashima et al. in 2017 (49). This pilot study was based mostly on extensive preclinical research performed by the same group (50). Patients with irreversible pulpitis had been recruited and adopted up for six months following DPSCs’ transplantation. Granulocyte colony-stimulating factor was administered to induce stem cell mobilization to enrich the stem cell populations. The research team reported that using DPSCs seeded on collagen scaffold in molars and premolars undergoing pulpectomy was secure. No opposed occasions or toxicity have been demonstrated in the clinical and laboratory evaluations. Positive electric pulp testing was obtained after cell transplantation in all patients. Moreover, magnetic resonance imaging of the de-novo tissues formed in the foundation canal demonstrated similar outcomes to normal pulp, which indicated profitable pulp regeneration. A distinct group conducted a clinical trial that recruited patients diagnosed with necrotic pulp. Autologous stem cells from deciduous teeth were employed to induce pulp regeneration (51). Follow-up of the cases after a yr from the intervention reported evidence of pulp regeneration with vascular provide and innervation. As well as, no signs of hostile effects have been observed in patients receiving DPSCs transplantation. Both trials are proceeding with the next phases, nonetheless the outcomes obtained are promising.

Periodontal tissue regeneration

Aimetti et al. carried out a study which included eleven patients affected by chronic periodontitis and have one deep intra bony defect in addition to the presence of 1 very important tooth that needs extraction (52). Pulp tissue was passed via 50-µm filters in presence of collagen sponge scaffold and was adopted by transplantation in the bony defects brought on by periodontal disease. Both clinical and radiographic evaluations confirmed the efficacy of this therapeutic intervention. Periodontal examination, attachment stage, and probe depth confirmed improved results along with significant stability of the gingival margin. Moreover, radiographic analysis demonstrated bone regeneration.

Regeneration of mandibular bony defects

The primary clinical study using DPSCs for oro-maxillo-facial bone regeneration was conducted in 2009 (53). Patients in this research suffered from extreme bone loss following extraction of third molars. A bio-complex composed of DPSCs cultured on collagen sponge scaffolds was applied to the affected sites. Vertical restore of the damaged space with complete restoration of the periodontal tissue was demonstrated six months after the remedy. Three years later, the identical group printed a report evaluating the stability and high quality of the regenerated bone after DPSCs transplantation (54). Histological and superior holotomography demonstrated that newly formed bone was uniformly vascularized. However, it was of compact kind, quite than a cancellous kind which is normally the type of bone on this area.

Stem cells for therapy of Sjögren’s syndrome

Sjögren’s syndrome (SS) is a systemic autoimmune illness marked by dry mouth and eyes. A novel therapeutic strategy for SS. utilizing the infusion of MSCs in 24 patients was reported by Xu et al. in 2012 (55). The strategy behind this therapy was primarily based on the immunologic regulatory functions of MSCs. Infused MSCs migrated towards the inflammatory sites in a stromal cell-derived factor-1-dependent method. Results reported from this clinical trial demonstrated suppressed autoimmunity with subsequent restoration of salivary gland secretion in SS patients.

Stem cells and tissue banks

The power to bank autologous stem cells at their most potent state for later use is a necessary adjuvant to stem cell-primarily based therapies. To be able to be considered valid, any novel stem cell-based therapy must be as efficient because the routine therapy. Thus, when appraising a kind of stem cells for utility in cellular therapies, issues like immune rejection should be averted and at the same time giant numbers of stem cells must be readily out there earlier than clinical implementation. iPSCs theoretically possess the ability to proliferate unlimitedly which pose them as a lovely supply to be used in cell-primarily based therapies. Unlike, adult stem cells iPSCs potential to propagate doesn't decrease with time (22). Recently, California Institute for Regenerative Medicine (CIRM) has inaugurated an iPSCs repository to offer researchers with versatile iPSCs cell strains with a view to speed up stem cell therapies by way of finding out genetic variation and disease modeling. Another vital supply for stem cells banking is the umbilical cord. Umbilical cord is immediately cryopreserved after start; which permits stem cells to be successfully stored and prepared for use in cell-based mostly therapies for incurable diseases of a given people. However, stem cells of human exfoliated deciduous teeth (SHEDs) are extra engaging as a source for stem cell banking. These cells have the capability to differentiate into additional cell varieties than the rest of the grownup stem cells (56). Moreover, procedures involving the isolation and cryopreservation of those cells are un-sophisticated and not aggressive. An important advantage of banking SHEDs is the insured autologous transplant which avoids the potential for immune rejection (57). Contrary to cord blood stem cells, SHEDs have the ability to differentiate into connective tissues, neural and dental tissues (58) Finally, the ultimate purpose of stem cell banking, is to ascertain a repository of excessive-quality stem cell strains derived from many individuals for future use in therapy.

Current regulatory tips for stem cell-based therapies

With the increased number of clinical trials using stem cells as therapeutic approaches, the necessity for growing regulatory guidelines and requirements to make sure patients security is turning into increasingly important. However, the fact that stem cell therapy is somewhat a brand new domain makes it topic to scientific, moral and authorized controversies which are but to be regulated. Leading countries in the field have devised pointers serving that objective. Recently, the Food and Drug Administration (FDA) has launched regulatory tips to make sure that these therapies are protected and efficient (59). These pointers state that; treatments involving stem cells that have been minimally manipulated and are intended for homogeneous use do not require premarket approval to return into motion and shall solely be subjected to regulatory tips in opposition to illness transmission. In 2014, a radical regulatory reform in Japan occurred with the passing of two new legal guidelines that permitted conditional approval of cell-primarily based treatments following early part clinical trials on the condition that clinical security knowledge are provided from a minimum of ten patients. These laws permit skipping most of the standard criteria of clinical trials in what was described as "fast observe approvals" and therapies had been categorized in accordance with danger (60). Thus far, the therapies that acquired conditional approval include those targeting; spinal-cord damage, cardiac disease and limb ischemia (61). Finally, regulatory authorities are actually demanding software of standardization and security regulations protocols for cellular merchandise, which include the use of Xeno-free tradition media, recombinant progress elements in addition to "Good Manufacturing Practice" (GMP) culture supplies.

Challenges & ethical issues dealing with stem cell-primarily based therapies

Stem cell-primarily based therapies face many obstacles that have to be urgently addressed. The most persistent concern is the moral conflict concerning using ESCs. As beforehand talked about, ESCs are far superior relating to their potency; nonetheless, their derivation requires destruction human embryos. True, the discovery of iPSCs overcame this concern; nevertheless, iPSCs themselves at present face another moral controversy of their very own which addresses their limitless capacity of differentiation with concerns that these cells might in the future be utilized in human cloning. Using iPSCs in therapy is still thought of a excessive-risk therapy modality, since transplantation of those cells might induce tumor formation. Such challenge is at present addressed through growing optimized protocols to make sure their security along with growing global clinical-grade iPSCs cell lines earlier than these cells can be found for clinical use (61). As for MSCs, these cells have been universally considered safe, nonetheless continuous monitoring and prolonged follow-up needs to be the focus of future analysis to avoid the potential for tumor formation after therapies (62). Finally, it may very well be postulated that one of the vital challenging moral points confronted in the sphere of stem cell-based mostly therapies in the intervening time, is the increasing number of clinics offering unproven stem cell-based mostly remedies. Researchers are thus morally obligated to make sure that moral considerations will not be undermined in pursuit of progress in clinical translation.

Conclusions

Stem cell therapy is turning into a tangible actuality by the day, thanks to the mounting analysis performed over the past decade. With every analysis conducted the prospects of stem cells applications elevated regardless of the many challenges confronted. Currently, progress in the sector of stem cells is very promising with stories of clinical success in treating various diseases like; neurodegenerative diseases and macular degeneration progressing quickly. iPSCs are conquering the field of stem cells analysis with infinite prospects of treating diseases using patients personal cells. Regeneration of dental and periodontal tissues using MSCs has made its option to the clinic and soon enough will change into a sound therapy. Although, challenges might seem daunting, stem cell research is advancing quickly and cellular therapeutics is quickly to be applicable. Fortunately, there are at the moment great efforts exerted globally in the direction of organising regulatory guidelines and standards to ensure patients security. Within the near future, stem cell-based therapies shall considerably impact human well being.

Acknowledgments

Funding: None.

Ethical Statement: The writer is accountable for all points of the work in ensuring that questions associated to the accuracy or integrity of any a part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.Zero International License (CC BY-NC-ND 4.0), which permits the non-business replication and distribution of the article with the strict proviso that no modifications or edits are made and the original work is correctly cited (including hyperlinks to each the formal publication by way of the related DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Footnotes

Conflicts of Interest: The author has accomplished the ICMJE uniform disclosure kind (accessible at http://dx.doi.org/10.21037/sci-2020-001). The creator has no conflicts of interest to declare.

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