During the last decades, the term “drug delivery systems” (DDSs) has almost fully replaced previously used terms, such as “dosage forms”, in an attempt to emphasize the importance of the drug carrier in ensuring the claimed safety and effectiveness of the product. However, particularly in the case of delivery devices, the term “system”, which by definition implies a profound knowledge of each single part and their interactions, is not always fully justified when using the DDS term. Within this context, dry powder inhalers (DPIs), as systems to deliver drugs via inhalation to the lungs, require a deep understanding of the complex formulation–device–patient interplay. As of now and despite the progress made in particle engineering and devices design, DPIs’ clinical performance is limited by variable patients’ breathing patterns. To circumvent this pitfall, next-generation DPIs should ideally adapt to the different respiratory capacity of individuals across age, health conditions, and other related factors. In this context, the recent wave of digitalization in the health care and industrial sectors may drive DPI technology towards addressing a personalized device–formulation–patient liaison. In this review, evolving technologies are explored and analyzed to outline the progress made as well as the gaps to fill to align novel DPIs technologies with the systems theory approach. A thorough literature search in Science Direct and PubMed databases evidenced a significant rate increase over the last decade of publications on dry powder inhalers (DPIs), confirming a constant growth of the interest in inhaled medicines. At the same time, several market reports predict a similar growth in the pulmonary administration route, due to an increase in respiratory disease incidence and the need for more effective combination therapies ,2,3. TheAlong with traditional products, smart technologies are emerging to satisfy specific market requirements for cost-effective innovation. In this regard, digital systems have already vehemently penetrated the inhaler market, carrying notorious advantages in the prevention of device use errors. In fact, microprocessors are increasingly implemented in inhalers to assist the patient in proper device handling, with a positive impact on compliance and product satisfaction. However, a real breakthrough in next-generation inhalers may result from the application of smart technologies, allowing device performance to be tailored based on a patient’s variable breathing patterns, while providing user-friendly features and preventing, compensating for, and/or recording potential handling and actuation errors.Among all the available technologies, the soft mist platform is worth citing due to its patient-centered approach and innovative technology, which is challenging the pressurized metered-dose inhaler (pMDI) and DPI market, thus placing it under the spotlight as a future growth driver .In spite of the winds of change in the inhalation device market, the global inhalers scenario is still lacking innovative technologies for a number of reasons that this review attempts to examine and discuss, with a specific view on DPIs. Moreover, we provide the reader with an updated prospect on the DPI digitalization market as well as shedding light on the application of novel smart technologies and the required steps ahead.DPIs are systems capable of delivering a particle-type formulation of an active pharmaceutical ingredient (API) for local or systemic effect via the oral–pulmonary route. They have gained attention as a valid alternative to nebulizers and pMDIs and are currently preferred for the treatment of chronic respiratory diseases ,7. DPIs DPIs are complex systems and their clinical performance depends on fully addressing the harmonic interaction between three important aspects that must be taken into consideration during development: (i) the physico-chemical and engineering properties of the powder formulation; (ii) the design of the device, with a special emphasis on its powder deagglomeration and dispersion capabilities; and (iii) ideally, the strength/pattern of each patient’s inspiratory airflow . TM technology  represents a significant breakthrough in the scenario of engineered inhalable particles. It enables fabrication of low-density, porous particles with a characteristic sponge-like morphology and reduced interparticle cohesion, with improved drug loading (as high as 90% w/w), lung targeting, and dose consistency [® , consists of a DDS-based on fumaryl diketopiperazine microparticles, which are self-assembled in a mild acidic medium to form microspheres with high porosity and surface area that can be administered without the addition of carrier particles [From a formulation point of view, the powder physico-chemical/engineering properties—namely particle size, particle morphology, hygroscopicity/moisture content, and surface electrostatic charge—are known to determine the particles’ fate and deposition pattern upon inhalation . Such pasistency . Anotherarticles . ® , devices technology has continued to evolve, and more than 40 different types of devices are currently available on the market [® and Rotahaler® , are breath-actuated single-unit dose devices, whereas second-generation devices are multi-dose reservoir-type devices, such as Turbohaler® , Easyhaler® , Ultrahaler® , and MAGhaler®  or multi-unit dose devices, such as Diskhaler® , Aerohaler® , and Eclipse® . Despite their higher cost of production, multi-unit inhalers are likely to ensure better dosage uniformity and a formulation’s chemical stability compared with multiple-dose devices [®  is a novel, breath-actuated, multi-unit dose device that provides accurate dose metering and releases the dose only when an inspiratory flow threshold of 35 L/min is reached [®  is an active piezoelectric-based DPI that is actuated on sensing a certain inspiratory flow threshold, whereas Aspirair®  and ResQhalerTM  employ compressed air as a powder dispersion source [®  platform is an active powder aerosolization engine that can be incorporated into various DPIs [The successful delivery of drugs into the respiratory tract is dependent in part on the integration between device design and formulation. Since the introduction of the first DPI, Spinhalere market ,19. Theye market . First-g devices . Recent  devices . NEXThal reached ,24. Newe reached ,26. Micrn source ,27. The ous DPIs ,29,30. Currently available DPIs vary in aerosolization performance and the fraction of delivered dose in the lungs ranges from approximately 9% to 80% . This hiUnfortunately, approximately 22–78% of patients with asthma and COPD and 31–53% of CF patients are poorly adherent to their inhaled medications ,37. ErroAddressing bioavailability/bioequivalence (BA/BE) issues of pharmaceutical products is a critical task for pharma companies. While well established for most oral products—for which the proliferation of the generics market has allowed the exclusivity extension for well-known blockbuster drugs—the issue of BA/BE assessment has only recently been revived as well for orally inhaled and nasal drug products (OINDPs), in light of the patent expirations of a number of landmark inhalation products.As a consequence, regulatory agencies have focused a great deal of attention on drafting proper guidelines on quality and safety as well as on the BA/BE of inhaled products ,48,49,50An issue worth mentioning though is the different view of the BE problem that persists among the major regulatory agencies. The Food and Drug Administration (FDA) and Japan Ministry of Health recommend comprehensive in vitro–in vivo and clinical characterization to support BE, while the European Medicines Agency (EMA) advises a stepwise BE assessment and accepts in vitro studies provided that there is a total match, in particular in delivered dose uniformity and aerodynamic particle size distribution, between the innovator and the generic . Other aSuch differences raise barriers to BA/BE assessment of inhaled medicines that grow even higher when considering next-generation devices. As will be better discussed later in this review, although new technologies are encouraged by some regulatory agencies, they are not adequately supported by standardization and struggle to find their place in the regulatory framework. This is worsened by the complexity of DPI products, in which device and formulation attributes must converge to provide the target performances. Therefore, both sides should be considered when addressing BA/BE of DPIs. However, guidelines still have a traditional view of DPIs, missing aspects related to technology integration and innovation. Beyond this, the R&D world of inhalable dry powders suffers from years of stagnation in powder engineering, to which the lack of adequate research on new excipients for pulmonary drug delivery has given substantial contribution. To prove it, the current list of accepted materials is limited to lactose, mannitol, glucose, trehalose, phosphatidylcholines, and magnesium stearate . While technology is moving fast with the increase in novel, integrated, alternative Good Manufacturing Practice (GMP)-ready approaches that combine next-generation analytical and modeling skills , regulatIn this regard, beyond recent progress , animal Confirming the above, Montgomery et al.  questionKhoubnasabjafari et al.  recentlyConfounding is a real problem in clinical trials for DPIs in particular, where the risk of errors in inhaler handling by the patient can be high. Discerning patient’s handling errors from actual clinical effects is not easy, especially in phase III trials where assistance and support to patients cannot be granted. Here is where digital systems can really make an impact by allowing monitoring and control over all phases of clinical studies . How digIn light of all the above considerations, two interrelated critical questions arise: Is there space for novelty in inhaled medications? If yes, which would/should be the direction? In this regard, digitalization is a fast growing and promising technology that could support patient-centered care, while offering realistic solutions not only for patients, but also for healthcare providers and pharma companies. Digital technology can improve clinical outcomes by enhancing adherence and minimizing a patient’s errors through cell-phone applications connected with the device, which provide useful tools such as reminders and step-by-step guidance for the proper usage technique. From the other side, physicians can track in real time a patient’s compliance to the therapeutic regimen or symptom worsening and consequently prevent severe disease exacerbations and improve the patient’s quality of life . This isAs mentioned above, for drug–device combinations, and particularly for inhalation products, errors related to patient device usage and delivery variations, as well as defective data collection, may provide distorted information concerning therapeutic efficacy in clinical trials . Hence, ® Adaptive Aerosol Delivery (AAD®) device , AKITA® , and AeroEclipse®  were launched. They ensured optimal drug delivery by detecting a patient’s breathing pattern and releasing the aerosol only during the inspiratory phase, thus preventing losses during exhalation, for which conventional nebulizers are notorious [“Smart” inhalers, as termed in the related literature, which provide reliable and objective feedback mechanisms regarding medication adherence and inhalation technique, have been added to the existing therapeutic arsenal for the treatment of chronic respiratory diseases—namely, asthma, COPD, and CF. They can be divided into two categories: add-on devices, in which the e-module is externally attached to the inhaler, and originally integrated devices, in which the e-module is incorporated inside the device . Their dotorious ,76,77,78TM , Smart Mist® , MDILogTM , Smart Inhaler Tracker , and Smart TrackTM  were some of the first digitalized pMDIs [® device  introduced further innovation, embedding Global Positioning System (GPS) functionality, which enabled detection of the exact location where patients experienced asthma exacerbation episodes and thus mapped high-risk areas and potential environmental triggering factors [® add-on sensors are compatible with a wide range of pMDIs, such as Flovent® , Dulera® , QVAR® , and Ventolin® HFA  [®  [® , for which the pharmaceutical company had previously marketed an FDA-approved device, the SmartTouchTM  for Symbicort® in collaboration with Adherium Ltd. . FindAir ONE , a “smart” add-on device for pMDI inhalers, was launched in the European market in 2019 and provides, among other benefits, useful information regarding the pollen level, air quality, and weather conditions, to help asthma patients predict an asthma attack-promoting environment [Dosered pMDIs ,107. Excord, UK) . In 2015Germany) . In 2020ironment ,91. Furtironment ,111.As discussed hereafter, the research and development of “smart” pMDIs has paved the way to the development of digital DPIs .® sensors dedicated to Diskus® , Ellipta® , and Neohaler®  received FDA approval in 2015, 2016, and 2018, respectively [® Breezhaler®  approval for all EU member states, as well as the UK, Iceland, Norway, and Liechtenstein [® sensor that can be attached to the base of the inhaler and that records actuations as well as the whirring noise of the spinning capsule during inhalation [® app via Bluetooth [Although first conceived as pMDI sensors, the PP has recently received FDA clearance as add-on sensors for DPIs as well. Propellerectively ,109,119.tenstein . It is itenstein . The opthalation . The senluetooth . In addiluetooth .® solution  in the US, after its FDA 510(k) over-the-counter clearance to enable sales direct to consumers [® app on a mobile device, where patients can set up specific reminders and track medication usage [® sensor able to capture physiological data as well [® add-on sensors dedicated to Diskus® (SmartDisk™) and Handihaler® (SmartHandy™) were recently launched [In 2018, Adherium Ltd. launched the Hailieonsumers . It invoon usage . In June as well . Hailie®launched .®, Nexthaler®, and Ellipta® [On the European side, Respiro was approved by the EMA and received the European Conformity (CE) mark in 2018. The Respiro digital health platform consists of a sensor able to monitor device usage and to help patients to adopt correct actuation maneuvers. Respiro was marketed the same year for three different products: SpiromaxEllipta® .Another add-on device that has been evaluated in different studies and trials ,126,127 ® technology officially entered the digital world in 2020, when Aptar Pharma acquired the Cohero Health portfolio [® DPI as a reminder to ensure patient adherence to a therapeutic regimen. The sensor also records and monitors actuations once it is connected via Bluetooth to the BreatheSmart app [The Diskusortfolio . Cohero mart app .In the early 2000s, a digital version of a well-known product, the Advair Diskus DPI, was tested by adding Diskus Adherence Logger add-on sensor technology , which wAnother add-on device is the Verihaler, also developed for pMDIs . It inco® Digihaler® is a digital rescue inhaler approved for use in four-year-old and older patients to treat or prevent bronchospasm with reversible obstructive airway disease, such as asthma and COPD, and for the prevention of exercise-induced bronchospasm [® Digihaler® has a dose counter attached to the actuator, which at the beginning of the treatment displays the number 200, which corresponds to the total available actuations. When the dose counter reaches 20, the color of the numbers changes to red, whereas when the dose counter reaches 0, the whole background color changes to solid red [® “family” was expanded with the approval by the FDA of two digital products: the AirDuo® Digihaler® and the ArmonAir® Digihaler® in 2019 and 2020, respectively. They are indicated for the treatment of asthma in patients aged twelve years or older. The AirDuo® Digihaler® can be used for symptom control, such as wheezing, whereas the ArmonAir® Digihaler® is indicated for longer-term treatment [® Digihaler®.Teva Pharmaceutical Industries Ltd.  obtained FDA approval in 2018 for the first all-in-one digital DPI with built-in sensors and Bluetooth technology . The Prochospasm . It incochospasm . The prechospasm . The prechospasm . ProAir®olid red . In addiolid red . The devolid red . In thisolid red . A pilotolid red . Overallolid red . The Digreatment ,114. TheIn 2020, Respiro was integrated into the well-known RS01 single-dose DPI to produce the digital RS01X DPI . It trac® family and RS01X complete the existing portfolio of marketed integrated DPIs. However, other digital DPIs with built-in technology and noteworthy features have been also developed. To the best of our knowledge, the DigihalerMore specifically, the USSC-03 device is manufactured as an electronic system able to monitor time, date, and inhalation profile to evaluate treatment adherence. It is provided with a sensor able to measure the pressure drop inside the device so that the blister is not opened until a pressure drop of about 1.5 kPa is detected. This allows wrong powder deposition following a poor inspiratory act to be avoided ,129. ® as a reference product in asthmatic children [®, but with a superior potential in handling pediatric patients as well as patients with low inspiratory capacity.Another product with distinctive features is the Inspiromatic™ DPI. Noteworthy advancement results from its active DPI features, being equipped with a powder fluidization system activated at low inhalation flow rate (7 L/min) and a data logger to record patient’s performance. It was evaluated in a comparative study against Aerolizerchildren . This ac® and Breezhaler® are devices with a long market tradition that are under development to go digital. In particular, the first paper reporting the use of an electronic Diskhaler dates back to 1997, when it was used to study treatment compliance in asthmatic adults [® [The Diskhalerc adults . This smc adults . The eledults [®  is slighDPIs are considered drug–device combination products by the EMA, which recently issued a draft guideline on the quality requirements for drug–device combinations ,143. BasIn Japan, medical devices are regulated by the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products and Cosmetics, effective since November 2014 . To dateSince 31 January 2020, the UK was formally out of the EU, but the European pharmaceutical law continued to apply to the UK until the end of 2020. Brexit had a strong impact on the EMA, which worked hard since March 2019 to relocate physically to Amsterdam and to avoid medicine shortages as much as possible. The EMA also issued guidance for companies involved in Brexit. Inhalers or medicinal product–medical device combinations produced in the UK would need to be tested in European facilities in order to be released in Europe as imported products, since the UK is now considered to be a separate country. All of these aspects have to be followed carefully, with substantial reference to the official website of the EU and UK governments ,160.Another aspect, not closely related to the regulation of digitalized products but of paramount importance, deals with the protection of sensitive information of patients who have to be monitored . In thisTerms such as “smart” DDSs and the like, while technologically feasible today, should be used with caution, since they reflect a product’s clinical performance in the real world, once approved and commercialized.We believe that now is time to define what “smart” really means when referring to pharmaceutical products and devices at the health system level, and thus, regulatory guidelines should be put forward for discussion and expedited adoption of such a concept.There is a well-recognized gap between what is recorded in clinical trials before marketing authorization of drug products compared with post-approval evidence, which negatively affects the safety/effectiveness index of drug products. This “lost in translation” scientific drawback has to be bridged with advanced tools such as artificial intelligence (AI) and Big Data, as defined in the Industry 4.0 wave of change. Inhalation devices could be a starting point for delivering real advancements in filling the gap between efficacy and effectiveness for patients’ benefit. In this regard, substantial contribution could stem from the growing arsenal of DPI digital functions that, as summarized above and in The “smart” definition and its proper use in pharmaceutical products. This term and its equivalents should be used only when meeting predefined conditions set by the regulatory authorities. Silverio-Fernández et al.  contribuThe Internet of Things (IoT) aspect of “smart” coupled with AI and machine learning capabilities will eventually be a change driver in transforming the currently passive and deferred pharmacovigilance system to an active one, permitting real-time evaluation and interventions for assuring continuous monitoring of the safety/effectiveness index of drug products across their lifecycle.The health system will be able to pay suppliers based on real-world valid data, relating the pricing/reimbursement schemes with the pragmatic performance of DDSs.This will also change the landscape of clinical trials, as they will be on-going through a product’s lifecycle and data will be shared by the patient with all concerned parties under real-time conditions.unmet needs due to the absence of commercial interest and limitations of science” and that “research priorities should be aligned to the needs of patients and health systems”. To overcome this gap quickly and efficiently, many aspects need to be changed both at the tactical level and strategy-wise. In spite of the current rush toward personalized medicine, most inhaled products are developed in a non-patient-centered fashion without accounting for actual individual needs. Therefore, greater effort should be focused on the understanding of patients’ unmet needs rather than the researchers’ citation portfolio. This is the transformation that must be “technologically” driven when designing next-generation inhalation devices. A “smart” device should facilitate real solutions for a given patient need, one that is not “invented” in order to “justify” a novelty claim. The implemented “smart” technology is an input in the whole process, which when interacting with other factors, such as selection of API, excipients, and device design, enhances the DPI’s capacity to address a real unmet need. Reviewing the “European 2020 Pharmaceutical Strategy” and its updates, it is now officially recognized that there are “Given the thousands of publications related to inhalation delivery, perhaps it is time to reconsider how many of them have actually contributed to practical advancements by impacting patient lives. The advantage of the scientific community being “data super-rich” is at the same time its problem because its abundance hampers the transformation of this big basket of a myriad of mixed data into pharmaceutical products and services that are valuable to patients. Within this context, we propose a series of assertions to be considered by health community experts and patient advocacy groups as a “starting seed” to raise awareness and discussion:Last but not least, the establishment of the smart concept will also allow the definition of quality in pharmaceuticals to be corrected. In fact, in regulatory guidelines the terms “quality”, “efficacy”, and “safety” are proposed as separate terms; thus, their obvious interconnection is missing, while it is scientifically absolutely solid that quality equals safety and effectiveness.Redefine the scope and stay tuned with the patient’s unmet needs. The one who is responsible for imparting this new message is the scientist, who through deep knowledge and high ethics has to carefully listen to patient’s needs so as to quickly address them.These needs have to be communicated, discussed, and adopted by the scientific community. There are a lot of meetings, many of them financially supported by the EU, which could easily serve this purpose. A clear “position paper” has to be constructed to effectively communicate these unmet needs of patients to health system stakeholders in real time.This “consensus paper” should be an official “compendium”, like the pharmacopoeias, which every stakeholder consults and has to comply with before designing a new inhalation product or an extension of an approved one.nth copy product of the original.The regulatory authorities have to adopt this as a “gold standard”, to differentiate the submissions needing attention and priority from those that are the mere HTA committees should make this “standard” visible to all stakeholders and make clear that the health system will only pay for the real, scientifically solid, delivery of value to the patient and not for a “copy and paste” approach. This is a major paradigm shift for paying for the value delivered to the patient and not paying based on sales volume discounts.Redefine, at the regulatory level, the definition of quality. It is not rational to adopt in a regulatory document a “chemistry-oriented” definition, which never existed in the related literature on quality, but instead to promote the quality-by-design initiative, in which quality is presented correctly, as was proposed by Juran three decades ago. Moreover, as our understanding of the gaps is progressing, the term “efficacy”, reflecting what is achieved in clinical trials, has to be replaced with the term “effectiveness”, which underlines what is realized after a product’s approval, under real-world conditions. This means adopting the correct approach, which is that quality equals safety and effectiveness, with the note that quality is continuously monitored, in real time, over the whole product lifecycle. The regulatory list of what is called “quality guidelines” has to be revisited and the first guideline, to start the journey towards fulfilment of the patient’s unmet needs, should be the “Pharmaceutical Quality System” known as International Council of Harmonization Q10 (ICHQ10). This guideline should also be revised based on the following two recommendations. The first should be a precaution to readers “not to proceed with the study of the rest of quality guidelines if ICH Q10 (now as ICHQ1) is not fully understood”. The second is to bring on a brief, but well-presented introduction to “systems theory”, which must be implemented as a prelude to the pharmaceutical quality system.In health systems there is at least one paradox. The two ends of the pharmaceutical supply chain are represented by the producer on the one side and the patient on the other side, supported by regulatory agencies and HTA committees. Being actual payers for the delivered therapeutic value, patients should be pivotal leaders. If so, health authorities should set a new array of standards as defined above. Particularly, payers should be in the position to entrust manufacturers to supply an inhalation device which, among the other known regulatory requirements, is capable of maintaining optimal delivery performance regardless of a patient’s breathing patterns. This is a standard practice adopted in other fields, where governments pay manufacturing companies for the development of specific technological solutions. The above mentioned scheme could also be applied to publicly funded research programs in the health sector. The technological/digital evolution of DDSs has to be translated into inhalation devices in a way that substantially improves their clinical performance in comparison with the current state of the art. To achieve this, in our opinion the following are fundamental steps in order to identify the gaps to be filled with “next-generation” devices:W.E. Deming coined a very important laconic phrase: “No aim? No System!” It is now time for the so called “patient-centered approaches” to be translated into realistic health solutions. The above aim being clear, the strategy of the pharmaceutical industry and researchers should assure the satisfaction of predefined unmet medical needs. The payer should take the lead in setting the therapeutic targets to be met and success should be measured against publicly pre-announced requirements that reflect the scientific gaps to be filled for patient’s benefit.Within this context the digitalization era in the health system should be framed and communicated to all concerned parties, and this has to be carried out by the regulatory bodies on behalf of the patients.Promoting and demanding real innovation with fast and reliable approval procedures for drug products that meet preset therapeutic targets; Assuring real-time safety and effectiveness of drug products in the pragmatic world of everyday clinical practice.Regulators should shift from an “auditing–monitoring” passive attitude to an attitude of being active health system players, re-writing and imposing the rules of the reimbursement schemes upon entirely new bases:The COVID-19 pandemic revealed specific weaknesses in the above context, and the intellectual power of academia along with the pharmaceutical industry should be aligned and focused on the diseases/clinical cases for which knowledge is insufficient or lacking. Recognizing and communicating what we do not know is the first and sincere step forward.This review, although it specifically tries to address the gaps in DPIs digitalization, comports with the authors’ intention to promote a broader debate as well so as to encourage a cultural change in the current approaches to the research and development of pharmaceutical products.


Myofascial Pain Syndrome (MPS) is a common, overlooked, and underdiagnosed condition and has significant burden. MPS is often dismissed by clinicians while patients remain in pain for years. MPS can evolve into fibromyalgia, however, effective treatments for both are lacking due to absence of a clear mechanism. Many studies focus on central sensitization. Therefore, the purpose of this scoping review is to systematically search cross-disciplinary empirical studies of MPS, focusing on mechanical aspects, and suggest an organic mechanism explaining how it might evolve into fibromyalgia. Hopefully, it will advance our understanding of this disease.Systematically searched multiple phrases in MEDLINE, EMBASE, COCHRANE, PEDro, and medRxiv, majority with no time limit. Inclusion/exclusion based on title and abstract, then full text inspection. Additional literature added on relevant side topics. Review follows PRISMA-ScR guidelines. PROSPERO yet to adapt registration for scoping reviews.799 records included. Fascia can adapt to various states by reversibly changing biomechanical and physical properties. Trigger points, tension, and pain are a hallmark of MPS. Myofibroblasts play a role in sustained myofascial tension. Tension can propagate in fascia, possibly supporting a tensegrity framework. Movement and mechanical interventions treat and prevent MPS, while living sedentarily predisposes to MPS and recurrence.MPS can be seen as a pathological state of imbalance in a natural process; manifesting from the inherent properties of the fascia, triggered by a disrupted biomechanical interplay. MPS might evolve into fibromyalgia through deranged myofibroblasts in connective tissue . Movement is an underemployed requisite in modern lifestyle. Lifestyle is linked to pain and suffering. The mechanism of needling is suggested to be more mechanical than currently thought. A “global percutaneous needle fasciotomy” that respects tensegrity principles may treat MPS/fibromyalgia more effectively. “Functional-somatic syndromes” can be seen as one entity (myofibroblast-generated-tensegrity-tension), sharing a common rheuma-psycho-neurological mechanism. Chronic pain is a major cause of morbidity and has a significant impact on quality of life . MyofascMyofascial pain syndrome (MPS) is an entity that still lacks a clear definition. Some define it as a regional pain disorder , others In clinical practice MPS is often defined by multiple areas of musculoskeletal pain and tenderness associated with painful points . Pain isAlthough MPS and fibromyalgia are defined as separate entities, the two may co-exist or considerably overlap ,3. They Studies of fibromyalgia reveal odd findings e.g., complete resolution after laparoscopic surgery, and strong overlap with other conditions . Many theories exist for fibromyalgia, the most accepted and studied seems to be central sensitization, but no single theory seems to explain a wide range of empirical evidence, and the pathophysiology and etiology are still not clear. Treatments are insufficient, meanwhile patients suffer. This scoping review focuses on the organic mechanical aspects of myofascial pain with the hope it might advance our understanding of MPS and fibromyalgia, highlight gaps in current knowledge, and stimulate research in a less explored field. Findings will be presented with the purpose of understanding the elements relevant to MPS and fascia, in order to assemble them and discuss a suggested mechanism for MPS and fibromyalgia. The discussion is divided into two parts: part 1 focuses on MPS and suggests a theoretical mechanism , part 2 discusses empirical evidence in support of fibromyalgia as an entity driven by myofibroblast-generated-tensegrity-tension, as predicted by this model.A systematic search was held for multiple combinations of keywords in multiple databases. Keywords included: “fascia tension pain”, “trigger point satellite”, “fascia stiffness pain”, “Fascia Densification”, “trigger point densification movement”, “biotensegrity”, for all fields with no time limit; and for “Risk factors myofascial pain syndrome” only for title/abstract; Systematic reviews, meta-analyses and randomized controlled trials were searched in title or abstract for “myofascial pain syndrome”, “spinal mobilization sympathetic nervous system”, “sympathetic activity induced by pain” since 2015. The databases used were National Library of Medicine PUBMED (MEDLINE), COCHRANE, EMBASE, PEDro and medRxiv. Web of science was used to find items through a cited reference search. All searches were done between September 2020 and September 2021. Only items published in English were included. This work follows PRISMA guidelines for scoping reviews. PROSPERO yet to adapt registration for scoping reviews. A data charting form was used to abstract key data, as well as a summary document that was updated in an iterative process: that document evolved into this review. The systematic search yielded 979 items. After removal of duplicates (N = 221), 758 items were screened by assessing both title and abstract. Items off topic, foreign language, and in journal ranked Q4 were excluded (N = 364). For the remaining items (N = 394) a full text determination of eligibility was then performed. Four items were excluded from the systematic search because they were off topic. Final number of items included in systematic search was N = 390.www.uptodate.com and more studies from searching databases (n = 409). These side topics were not searched systematically. An attempt was made to cite more than one source in such cases. Further details on search method in supplementary material , “properties of fascia” (n = 47), “anatomy and movement” (n = 43), “nervous system” (n = 31), “biotensegrity” (n = 26), “myofascial pain treatment” (n = 209), “myofibroblasts” (n = 93), “fibromyalgia” (n = 93), “reviews” (n = 33), and “other” e.g., somatic syndromes, stress, chronic pain, Dupuytren’s disease, plantar fasciitis (n = 129). The systematic search included 127 clinical trials, 33 systematic review, and 19 meta-analyses. The findings are presented with the purpose of understanding the elements relevant to MPS and fascia, in order to assemble them and discuss a suggested mechanism of MPS and fibromyalgia. A microscopic view will set the stage for a macroscopic understanding.Fascia is an important yet often misunderstood tissue in medicine. Essentially, fascia is connective tissue composed of irregularly arranged collagen fibers, distinctly unlike the regularly arranged collagen fibers found in tendons, ligaments, or aponeurotic sheets . When coFascia has properties that enable it to reversibly change its stiffness and decrease the forces of tension experienced by it. This is a mechanical ’stress relaxation’ resulting from the viscoelasticity of fascia that expresses high or low stiffness, depending on the rate of loading. Some experimental tests demonstrate a 90% of stress relaxation achieved in about four minutes, afterwards the stress relaxation curve is near linear horizontal –23. OtheBlood vessels and nerves are interspersed in fascia, therefore, involvement of these structures due to fascial changes is commonly seen ,19. It iHyaluronic acid (HA) has a key role for fascia. It is the major glycosaminoglycan of the extracellular matrix (ECM) and a major constituent of connective tissue . Its conFascia acts as a key player for generating movement . AlthougNon-versatile movement patterns and sedentarism are an important lifestyle component for fascial changes and pain . A meta-The fact that fascia can transmit tension to a distance is a basis for a “bio-tensegrity” framework ,37. Bio-When the tension of fascia increases, the connective tissue can distribute the forces throughout the surrounding areas, propagating along the myofascial system ,18. The Acceptance of the concept that a fascial tensegrity system connects the whole body is not necessary for a scientific discussion of tension spreading to other areas of muscle groups or structures. Some studies indicate that a tensegrity model might not be a true representation of the whole fasciomusculoskeletal system, and some evidence supports tensional propagation only to certain areas .There are several phenomena that accompany MPS including: trigger points (TrPs), active loci, taut bands, satellites, and the local twitch response.Trigger points—Changes in fascia are associated with pain in TrPs and tender spots. Many patients with active  TrPs have other areas with the same electrophysiologic findings that are not symptomatic, called latent TrPs. Latent TrPs seem to only cause pain upon palpation, while active TrPs cause pain and symptoms both at the site palpated and referred elsewhere ,4,9. TheTheories of the origin of TrPs emphasize the chronic contraction associated with them or their tendency of appearing at the muscle spindle ,9. OtherTrPs are extremely common. Among 224 non-specific neck pain patients, TrPs were found in all of them . In studActive loci—TrPs show electrical abnormalities called ’active loci’. This is a small region in a muscle that exhibits spontaneous electrical activity (SEA), often characterized as endplate noise measured on electromyography (EMG), leading to chronic contractions . AlthougTaut Band—A taut band is thought to be composed of several TrPs and shows excessive endplate potential activity . SustainTrP Satellite—TrP satellites are another disputed aspect of MPS. Some literature states TrPs themselves can induce motor activity (referred spasm) in other muscles . IllustrVarious hypotheses have been suggested to explain the mechanism of MPS, among them are trigger points, non-muscular sensitization of the nervi nervorum, central nervous system, and several other theories ,7,9,50. Fascia itself is able to actively contract. Tensional alterations are caused by contractile cells . MyofibrNormal fibroblasts are highly sensitive to the physical stimuli. Tomasek et al.  show cerIt is also possible that myofibroblasts can couple their activity directly to other cells like myocytes via gap junctions and act as a unite ,53. InteSeveral pharmacological and non-pharmacological treatments are suggested in literature.Non-pharmacological ,11,54–57Pharmacological ,9–11,54:The discussion includes two parts. Part 1 discusses myofascial pain syndrome (MPS) and presents a suggested theoretical model which is based on the scoping and systematic literature search. Part 2 is based on part 1 and discusses implications derived from the model and further empirical findings in support of the main hypothesis predicted by this model.Synthesis of the data gathered in this review leads the author to the following analysis and suggested mechanism:There are three aspects of fascial induced pain to consider, from the standpoints of physics, biomechanics, and cellular biology. These seem relevant to fascial tension, TrPs, and MPS.The standpoint of physics relates to energy. Thermodynamically, the human body can be seen as an open system of energy, and so can the fascial system. Although energy and entropy are modulated by various factors, by nature, entropy of this system will spontaneously tend to increase. To tense the fascia energy needs to be expended. Once fascia is tense the energy can remain as potential elastic energy or change due to other modifications, for example molecular rearrangement. Hyaluronic acid (HA) has a molecular structure that enables it to have a high degree of entropy, like an entropic “sponge”. When entropy increases it generates osmotic pressure and diffusion of fluids and other processes. Thus, when entropy of HA increases, osmotic pressure increases, and stress decays. If stimulus is not removed after this acute stressing, fascia will remain in the failure part of the stress relaxation curve and will be remodeled in this state. Although entropy goes together with osmosis and stress decay, each oscillation between different energy states will likely cause a loss of energy being a non-ideal system, for example due to friction. Fascia has hysteresis and is not a perfect “energetic spring” to oscillate between high-tension and low-tension states, i.e., it dissipates energy.Secondly, from a biomechanical standpoint, the literature review shows that (i) simple stress decay and recovery from it is a reversible process due to elasticity of fascia; (ii) trigger points (TrPs) and myofibroblasts are found in normal individuals; TrPs are seen even in childhood and infancy, and in animals ; (iii) fThese suggest an underlying ongoing interplay between movement and sedentarism. Since tensional changes are reversible in fascia of normal individuals and depend on the mechanical state of the human body, this indicates fascia is meant to withstand and continuously undergo dynamic changes according to varying dynamic mechanical states. Since immobility often leads to collagen alterations, HA changes, myofibroblasts, and pain, we can see MPS as a natural consequence of the sedentary lifestyle. Resulting from the evolutionary “price” biology paid in a trade-off with chemistry when trying to “come up” with a tissue as effective, pliable, compliant and strong as the fascia. This “bargain” served us well to function effectively as an organism dominated by continuous movement. It seems that by living sedentarily, the natural disadvantages of the properties of fascia  manifest pathologically. Stiffness and lack of mobility of fascia has implications beyond a patient being unable to move adequately, it can affect the behavior of all cells interacting with the connective tissue matrix . If indeThe third aspect to consider is a cellular one: induction of myofibroblast by tension and by sedentarism ,51. ChroThree elements combined might help explain MPS. These are: (i) tensegrity, (ii) TrPs, and (iii) myofibroblast contraction and stress shielding.Manifestation of MPS is seen in TrPs. Latent TrPs may be points that have previously nociceptively sensed tension , due to sedentary behavior or a ’satellite’, and then were mechanically induced to stress shield themselves via myofibroblasts. The stress shielding does not necessarily eliminate tension (and pain) completely, thus preserving some mechanical drive for further proto/myofibroblast activity. Moreover, new myofibroblasts generate alpha smooth muscle actin (α-SMA) and contractions themselves . Over tiThese dynamics may be the basis for the unexplained “metastasis” of TrPs and satellites that Quinter et al.  refer toActivating a latent TrP is hypothesized to involve interference with the stress shield or stretch-activating myofibroblasts to rapidly contract, thus exposing the area to higher tension and initiate nociception. Eliminating a TrP seems to induce a local twitch response, which possibly signifies the neuron’s or muscle’s calcium driven response to a recovery from an active locus or shielded tension. Alternatively, it may be on-off “flickering” of the myotatic reflex due to nearby myofibroblast rapid MLCK contractions and their waves of calcium flux. Active loci may be a multifactorial phenomenon. For example, stress shielding (with or without gap junctions) superimposed on sympathetic activity, i.e., a myotatic reflex on top of sympathetic drive. It would seem plausible to expect one to “learn to relax” or “learn to cognitively override the sympathetic aspect by focusing attention", but not to willfully override a reflex response. The fact that muscle spindles are surrounded by a capsule of connective tissue, an area that sometimes might be palpated as a nodule  suggests that if there are microscopic tensions, they might possess a sensitivity to generate more tension at the spindle (via proto/myofibroblasts positive feedback), thus locking the stretch reflex to a certain degree. Locking the reflex would “turn on” an active locus in the associated muscle. To complicate the above, if electrical coupling of this structure occurs with an end plate , via myofibroblasts, it might perpetuate an “arrhythmic” picture on EMG, with background noise, and random spikes upon myofibroblast contractions. Mechanical disruption of this structure e.g., manipulative therapy, should unlock this pathology, at least partially. This might be one of the reasons for different degrees of body relaxation and the inability of some to experience it. If neurotransmitter molecules (or acetate) leak outside the synaptic cleft they might induce adjacent fibroblasts to transdifferentiate, which might explain why muscle overuse is associated with “TrPs” .“TrPs” and “tender spots” are therefore suggested here to be basically the same (driven by myofibroblasts), but different in their location and fascial layer. This notion is made under the now common presupposition that the main difference between the definition of “TrPs” and the definition of “tender spots” is radiation of pain. If a large nerve is affected by a nearby population of myofibroblasts that contract upon mechanical stimuli, it could radiate pain. If a large nerve is not affected by them, it might not radiate pain. If enough stress shielding and armoring has been created, nerves will be mechanically shielded from an external force applied to the tensegrity . Snapping palpation held longer would elicit more of a response . Thus, Notwithstanding, other factors are not excluded. Factors associated with the central nervous system could also be implicated in the genesis of MPS, as well as genetics, environmental factors, psychosocial aspects, chronic sympathetic “freeze” reaction to everyday psychological stress, etc. Based on this discussion, we might expect factors affecting fascial myofibroblasts to have potential to cause tension, pain, or even lead to MPS. For example, diet is believed to play a role in MPS , and stuIt is unclear where the tipping point between a status quo of movement-sedentarism and a deranged myofibroblast activity is. It is likely multifactorial, but lifestyle seems to be a major factor. A mechanical stimulus causes differentiation to myofibroblast ,74, someTrPs and myofascial pain, particularly when severe, can cause various symptoms that are not limited to the fascial-muscular-skeletal system. It is suggested that the sympathetic nervous system (SNS) causes TrPs . ReciproPeople with MPS fail to relax muscles due to a mechanical reason. Myofibroblasts can synthesize α-SMA fibers, which would transform fascia into a pseudo-muscular contractile tissue. It is not necessarily innervated and can remain contracted for years ,83. SincFinally, sedentary behavior and active lifestyle are widely emphasized in public health. However, much focus is dedicated to cardiovascular and metabolic aspects. This review sheds light on the link between lifestyle and pain and suffering. It is worth noting that the most common recommended treatment of MPS found in this literature review is mechanical, including needle insertion, movement , and massage/manipulative therapy. It helps treat MPS or reduce fascial related pain ,43,54–57Needling was found as a recurrent modality in literature. Needle treatment of TrPs increases pressure pain threshold . Three eSince needle insertion itself seems to relieve pain , this maThe more stress-shielding is present at the locus of insertion, the longer it should take for relief to happen. Stretch lesions along sensory nerves should be relieved too. This treatment acts like breaking the connections in a geodesic dome of the tensegrity model and then allowing for new healthier connections to form by natural remodeling. (The following video observations may help grasp this model –101) EliExamples in support of the suggested mechanism may have transpired in several studies. Three findings are briefly presented as follows. A study of 37 patients who were all diagnosed with plantar fasciitis and all had been treated with corticosteroid injection into the calcaneal origin of the fascia . All hadA second study encountered the same enigma: 68% of patients with plantar fasciitis had a sudden rupture associated with a corticosteroid injection. Although it relieved the original pain, these patients developed new problems: arch or midfoot strain, lateral plantar nerve dysfunction, hammertoe deformity, and stress fracture .These examples might suggest there is room for a more sophisticated strategy in treating the fascia instead of simply aiming and firing at the pain. Maybe this should be interpreted not as an adverse event, but as a testimony that the treatment modality undermines the tensegrity system. Conceivably, behind this is a release of fascia in an area of very high tension, causing too drastic of a change in the tensegrity structure, instead of approaching this tension gradually. A sudden change might shift the forces to other areas and exacerbate the imbalances , perhapsThe third finding that might be interpreted under these principles, is the phenomena of: “following a tooth extraction, a pain behind the ear and on the side of the face in the day or so prior to facial weakness often constitute the earliest symptom of Bell’s palsy”  . If corrIn conclusion, under the framework of tensegrity, it might be logical to first needle the dorsal foot and foreleg in plantar fasciitis, for example, assuming connective tissue is pulling the plantar fascia  and causing pain. Therefore, aiming to primarily treat the underlying tensional abnormality of fascia, and through this improving the symptoms of pain. Actually, it seems a TrP with severe localized pain may not be the source of pathological tension because myofibroblasts stress shield their area from tension: fascia is a living tissue that pulls rather than pushes. Treating only the painful point is expected to lead to an endless chase of migrating pain whose location is determined by dynamics of the tensegrity structure. Tension is likely to focus more near hard and angled surfaces that have sharp force-gradients; initially generating active TrPs (if a nerve is there to experience this) that have yet to sufficiently stress-shield themselves with a fiber web. By this rationale we may expect points to be concentrated more near areas of fascia adjacent to solid or bony edges . Tension will be present ,119, butThese conclusions may be part of the explanation to why these “functional” pain syndromes are epidemiologically so closely associated with one another , whPart 1 of the discussion focused on the theoretical model of “fascial armoring” formed based on the empirical evidence found in the systematic search and scoping review. A myofibroblast network generating tensegrity tension , when widespread, predicts further abnormalities. In this section empirical evidence is presented in support of fibromyalgia as a global chronic compartment-like syndrome driven by myofibroblast-generated-tensegrity-tension. Findings from various fields including cardiovascular, metabolic, musculoskeletal, integumentary, and surgical, are discussed.Studies show tissue stiffness is significantly increased around TrPs , and bloKatz et al.  found inA microdialysis study examined interstitial concentrations of metabolic substances in fibromyalgia . ConcentWachter et al.  quantifiOther body structures are also involved, among them are nerves. Perez-Ruiz et al.  found hiaction potentials to be fired. Action potentials that may even persist after the removal of the stimulus and high mechanical sensitivity are suggested by this (in vitro) study. More in vivo and in vitro studies suggest the same [Sugawara et al.  suggest the same –158. It the same . It is pWang et al.  find a bSeveral studies point to a peculiar phenomenon: Saber et al.  witness Oddly, why do the location and type of surgery seem to regulate the positive or negative impact on these somatic conditions? Indeed, it was suggested in this literature review that MPS/TrPs can cause chronic changes in bowel habits. Should we suspect that in these associated disorders, the connecting motif is connective tissue? This may imply that the location of the surgery has different effects on fascia, even remotely, due to- and regulated by- tensegrity forces. The lateral raphe and common tendon of the transversus abdominis are suggested to form connections between, and transfer tensions between the abdomen and the paraspinal muscles and sheath ,169. ThiNow, what is missing from current theories about fibromyalgia? On one hand, 21st century’s best physicians and psychotherapists are not enough for fibromyalgia to relinquish, while on the other hand, parathyroidectomy is. What do the surgeons do, even without special intent, that we haven’t tried? How to see that which is being overlooked? It appears this entity, or the tissue that is the veil, is responsive to surgery more than to opioids and anti-epileptics.According to central sensitization, is a parathyroidectomy able to fix the pain matrix? And can hysterectomy impair it? What about below knee amputation?More studies indicate fibromyalgia may include also easy bruising ,170, haiThere are several theories trying to explain fibromyalgia including: central sensitization and neuroplastic pain circuits, autonomic dysfunction, neuroendocrine and stress, social and psychological , and several more theories. Can they be the explanation of all these manifestations? Do psychosocial theories or somatization explain these? No single theory seems to fully account for fibromyalgia. For example :If it is sympathetic-parasympathetic dysregulation: why is muscle damping found to be increased unilaterally more often than bilaterally, why is postural hypotension not in the diagnostic criteria, and why is it strongly associated with sicca but lacks reports of chronic sialorrhea? Why urinary urgency but not retention, and how to explain empirical findings of autoantibodies?If it is inflammatory or autoimmune: where are the standard inflammatory markers, why is it so closely associated with irritable bowel syndrome of all conditions, and why does it respond to tricyclic antidepressants? What do the occiput, scapula, and knee possess, for example, that is absent from all interphalangeal joints and parietal bones? Are bone ridges a necessary-and-not-sufficient condition for tender points? What underlies the close association with acquired immunodeficiency syndrome , and whyA low-grade neuroinflammation might occur sub-clinically in fibromyalgia, but what drives it? The full cytokine profile of MPS and fibroblasts is not covered in this review, however, some studies suggest chronic myofascial pain is associated with, or causes, elevation of cytokines and inflammatory mediators, fibroblast growth factors, serum reactive oxygen species, and neuroendocrine signaling ,179–181.Is there any evolutionary sense for support of fibromyalgia as autoimmune? Cancer is rigid and is affected by connective tissue rigidity . SupposeCentral sensitization is the most accepted explanation: however, there are several questions that this theory does not seem to fully explain and some empirical findings that the theory did not seem to predict. How is fibromyalgia mechanistically different from “tension-type-headache”, “nonspecific-low-back-pain”, “nonspecific-neck-pain”, and “MPS”? What is the pathophysiological difference between “primary fibromyalgia”, “secondary fibromyalgia”, “secondary-concomitant fibromyalgia”, and “juvenile fibromyalgia”? Is fibromyalgia the same entity or different from “chronic widespread pain”? In terms of “fascial armoring”, there is no need to multiply entities, it remains myofibroblast-generated-tensegrity-tension, though, each tensegrity is different, anatomically. The fascial armoring model, intrinsically, has variations. Why does “chronic fatigue syndrome” (CFS) manifest with pain in tender points? Since fatigue is the predominant symptom rather than pain, it might indicate that deeper layers of connective tissue are more involved. How does the pathophysiology of fibromyalgia overlap with that of headaches and CFS, if searching for it only within the cranium? The boundary of an entity goes as far as the boundary of the cellular process that is behind it.Can central sensitization be resolved? If so, what is the modality and mechanism of action of the cure? In the long term, do opioids worsen the pathology? According to central sensitization, why prefer milnacipran, duloxetine, and pregabalin, but not venlafaxine, tramadol, or gabapentin? Is diet important? A pharmacological or nutritional agent that induces myofibroblasts is expected to be either ineffective or harmful in the long term in fibromyalgia. From the standpoint of “fascial armoring”, an antidepressant that induces myofibroblasts might have some positive side effects, e.g., improved mood.Will surgery exacerbate central sensitization, relieve it, or neither? What are tender spots and how does the topography remain conserved between individuals? These spots seem fundamental because fibromyalgia can be diagnosed based on them. Why two centimeters distal to the lateral epicondyle and not midway between the elbow and wrist? Will this topography change if there are congenital deformities in the brain/spine? What if a deformity in the elbow? Which is the constant that allows for the preservation of this point distribution? How do we know there is no peripheral organic cause for the pain if we haven’t looked at tensegrity? Is “post COVID-19 syndrome” similar, different, or is it the same? If the same, according to this model, COVID-19 should induce myofibroblasts. Which comorbidities interact best, and which are the worst for fibromyalgia, based on central sensitization, theoretically? One might offer multiple sclerosis, tetraplegia, adrenomyeloneuropathy, Cushing’s disease, or congenital adrenal hyperplasia. So then, why is Ehlers Danlos/hypermobility syndrome so closely related to fibromyalgia?The pathogenesis of peripheral and/or central nervous system changes in chronic widespread pain (CWP) is unclear, though, peripheral soft tissue changes are implicated . Some evPerhaps the relationship between fibromyalgia and hypermobility syndrome has to do with changes in ECM properties that induce myofibroblasts, thus initiating a widespread MPS cascade? Studies of patients with Ehler-Danlos/hypermobility syndrome find up to 70–100% have CWP and evidence supports a close association between hypermobility syndrome and fibromyalgia ,192. Of Psychological and social theories: evidence for the input of psychological/psychosocial factors and stress in the pathogenesis of fibromyalgia is suggested in studies . CognitiPsycho-emotional explanations are a double bind for fibromyalgia: if muscle tensions and contractions are psychologically induced by mental stress, how are they maintained chronically with such high intramuscular pressures if patients are often fatigued? On the other hand, if habitual psychological muscle contraction is what leads to the fatigue, why can’t they relax, and how do muscles contract independent of alpha and gamma motoneurons and extrafusal fibers? Would we not expect a combination of muscle relaxants and meditation to be more efficacious? What kind of an entity can be both systemic and unilateral? A sympathetic theory does not suffice, as stated by Wachter et al. . Fig 6 iIs depression a causal factor, and if so, why are antidepressants not more effective? Is there a global abnormality in tryptophan’s derivatives? Does physio-emotional Stress cause fibromyalgia, or does fibromyalgia cause physio-emotional Stress? At which stage, approximately, does the mechanism of this entity diverge from that of Stress, and why is it closely associated with Sjögren’s syndrome? Why pass over pancreatitis? And is there a prediction for the interaction with asthma, for example? The author could not think of an evolutionary rationale in having a self-destructive infinite positive-feedback of pain in two to six percent of a species, with no peripheral organic lesion, due to history of emotional trauma, or due to any reason. These entities were designed throughout evolution, no? Life must go on and we need to move for life to move on. Cancer uses fetal genes to multiply, cystic fibrosis is part of variety and selection, allergies are immune cells being overprotective, iron deficiency can cause pica, and COVID-19 is a big accomplishment for viruses. Why would the brain amplify pain with no organic lesion? Evolution might be offended; and treating that malady with exercise is not all intuitive either. The human mind is most complex but is not most frail. Is connective tissue a non-issue? Why is the focus specifically on pressure and pain? Does psychology navigate sensitization towards predetermined sensory tracts, or is there genuine sensory input of pressure arising from the periphery and causing central neurological adaptations? If the former- why those tracts? And if the latter- what drives the force that causes pressure in the periphery? The character structure? The tensegrity structure? Myofascial tissue? Does the reader know of any entity that can sustain generalized mechanical pressure with no obvious cause? For the sake of a scientific discussion, let us include any hypothetical entity as well.If fibromyalgia carries such a strong psychological component, why did a study find an odds ratio of 2.53 and effect size of only 0.51 for anxiety disorder in fibromyalgia, while for fasciitis and muscle spasms it found odds ratios of 5.27 and 6.05, with an effect size of 0.92 and 0.99 , respectively ? Does fi"Somatic” needs clarification: Is “fascial armoring” part of “Somatic”? There must be some pathophysiology to it because it obviously is not magic and any model that tries to tackle fibromyalgia’s pain cannot be shy of “Somatic”, too. To rely on “using imagination” in this case seems to be a weak attempt to simplify such a complex problem, no? Having schizophrenia seems to be different and unfortunately searching only inside cranium limits our options.  When excluding magic, imagination, and schizophrenia, what are we left with? A ghost in brain, or a shadow in fascia? Science is free to choose where best to look. Gupta et al.  studied Why and how does MPS develop into fibromyalgia? Is MPS also psychosomatic? Essentially, any answer to that would depend on our definition of “psychosomatic”. If “psychosomatic” has a peripheral factor involving myofibroblasts, then, the answer is: probably yes. Therefore, this model suggests that between a treatment that focuses mostly on the brain or one that focuses mostly on the tensegrity, the one focusing also on the tensegrity should be more effective, at least in the medium to long term. In other words, a combination of cognitive behavioral therapy and exercise with any current pharmacological treatment protocol, should be less effective than, for example, a combination of movement therapy, hyperbaric oxygen chamber therapy, psychotherapy, and minimally invasive therapy (tensegrity based needling). It also suggests that concentration of myofibroblasts and α-SMA in involved connective tissue should correlate better with the Fibromyalgia Impact Questionnaires than do frequency of pain catastrophizing or severity of emotional trauma. Has the reader ever felt an itching sensation, headache, or repeated muscle twitching, with no clear reason? Was it ever psychosomatic?There are those who suggest fibromyalgia is not a real entity or that it is caused by sleep disturbances . HoweverNoteworthy, two parallel mechanisms (or more) might be at work and are not necessarily incompatible with each other. Notwithstanding, if the mechanism starts in the fascia, and if we rarely study the fascia in fibromyalgia, how will we find the mechanism?How is it that multiple theories, even when combined, do not seem to fully explain this entity? Is there any tissue out there that all theories have overlooked? A tensegrity model is not without its questions: (i) How are depression and Lyme disease linked, and why is there wheezing, insomnia, and small fiber neuropathy? (ii) Self-mutilation?  (iii) DoDoes “fascial armoring” fill in gaps regarding some of these anomalies? If affecting the trunk, a constrictive tissue in the chest might be able to impair lung function and contribute to wheezing and chest tightness. If involving a compression by the cervical fascia, it might affect salivary ducts/glands, affecting salivation. In the neck and pretracheal fascia, muscle tension dysphonia. Temporal fascia, tension like headache. Periorbital, reduced optic disc perfusion. Wrist, carpal tunnel syndrome. Hand, Raynaud’s-like phenomena. Under the skin, crawling sensations. Pelvic fascia, urinary urgency. Abdomen, peristalsis. Myofibroblasts contract over hours to lock in tension in ECM , so, undThis theoretical model can only go as far as the cellular process that is behind it, so, what happens when modulating the cellular process? Interestingly, studies suggest certain antidepressants can downregulate myofibroblasts and ACTA2 gene expression ,205, whiA study suggested that in fibromyalgia, a global pathology involving tryptophan might come at the expense of other serotonergic operations such as in the brain . A mechaCan an imbalanced tensegrity structure be associated with an imbalanced mind? It is possible some individuals feeling persistent tension and crawling sensations might try self-mutilation in such a way that physically releases tensegrity tension, rather than actually attempting suicide. Consciously or unconsciously: similar to pica, mentioned earlier. Associating pica with iron deficiency, glucosuria with diabetes, and self-harm with a tensegrity abnormality, seems to be a better choice for Nature than the other way around. Pica with “fascial armoring” would have pointed the author towards the mind. Lacerations are probably the best first approach for this purpose and horizontal incisions might be more effective if vertical to force vectors. Unfolding this reason while using the scientific terms would be difficult for most common individuals, even for those with an extremely high body awareness; it would probably be described as: “trying to release a feeling”.Studies show obesity induced connective tissue fibrosis is dependent on mechanosensitive signaling . FibrosiIn any case, perhaps a treatment modality or prophylaxis that applies multiple needles in different areas of the tensegrity system, could be utilized as a global percutaneous needle fasciotomy. The theoretical end purpose for this treatment would be by passively inserting the needles and then allowing the network of cells to lower global fascial stiffness beneath the threshold necessary for myofibroblasts activity (~10–20 kPa) and slowly experience a tensional collapse. Each intrafascial  needling therapy would have to be adapted according to the current state of the tensegrity structure, meaning: one protocol does not fit all, and does not fit one all times. If we ignore tensegrity principles, pain might increase. Patience seems key because the longer the duration of severe disease, the slower the change should be made. Human physiology does not tolerate sudden changes well, and “the entropy must go somewhere”. The myofibroblast that remain would be responsible for the relapse, at least in part. Elastography studies of fibromyalgia and MPS are scarce. Some studies found fascia of patients with myofascial pain measures statistically significantly higher on shear wave elastography, and they have increased peri-muscular connective tissue thickness and ultrasound echogenicity ,242. It At least we might want to exclude an organic fascial cause before perceiving these cases as purely psycho-functional disorders, even if the full mechanism is still unclear. Is there enough empirical evidence to recognize MPS and fibromyalgia as honorable organic diseases, like any other? Internal medicine is used to entities that are either immune related, infectious, malignant, endocrine, metabolic, genetic, cardiovascular, neurologic, traumatic, or toxic, but not familiar with many mechanical ones. If medicine overlooked another system causing pain besides fascia, like integumentary or skeletal, it would probably lead to overlying on psychology to explain that pain. Maybe it is not some mechanism that has yet to be discovered or measured. Maybe it has been both discovered and measured yet overlooked and misinterpreted. It is difficult to explain all the empirical evidence relating to fibromyalgia  while relying on central sensitization and stress or somatization alone. Therefore, investigating a link between fibromyalgia and a peripheral mechanical process might benefit our understanding.The enthusiast of the principle of Occam’s razor  might consider seeing other functional entities that are known to be associated with pluripotent TrPs ,257,258,Based on this review, it seems that fascia is an intelligent and sophisticated tissue network, at least like any other tissue network we know. It is shown myo/fibroblasts have gap junctions that can couple and directly communicate with each other  and witOn a spectrum of “normality” we may all have “MPS” to some extent, technically speaking. It seems to be a question of how much we have and how much it affects our life. A tradeoff is still being made, no longer by biology but by humans. Not regarding the molecular design of fascia, but it is an ongoing tradeoff between not moving and moving. As it seems to be a natural condition worsened by an un-natural lifestyle, we may say living sedentarily misses our evolutionary target . It is interesting a study by Younger et al. finds patients with myofascial pain have changes in grey matter in the hippocampus, anterior insula, and cingulate cortex, among several areas : ForgettThe main limitation of this scoping review is that a sole researcher evaluated the studies. It is based on other empirical studies where some are in vitro studies, as mentioned in parts of the discussion. Being a scoping review, although a broad searching strategy was applied, not every topic was searched systematically. A systematic search was done for several main key phrases, in five databases. Systematically searching for relevant side topics  was not feasible, unfortunately. For side topics, an attempt to find a reliable source of information, like a textbook or study (or both), was the strategy to gather information. In such cases an attempt to cite more than one study was made. Worth noting, no on topic studies were found when searching “fibromyalgia myofibroblast” or “fibromyalgia alpha smooth muscle actin”. “Epigenetics and myofibroblasts” was not in the search. Kynurenine and the remaining 4% post-parathyroidectomy were not analyzed. The full cytokine profile and the topic of vitamin D in fibromyalgia was not discussed although a study finds vitamin D might play a role in myofibroblast attenuation or de-differentiation , and a mS1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


Stigmatization impedes the social integration of persons recovering from mental illnesses. Little is known about characteristics of the stigmatized person that lessen or aggravate public stigma.This study investigates which characteristics of persons with mental illnesses (i.e. with a depression or a psychotic disorder) might increase or decrease the likelihood of public stigma.Over 2,000 adults read one of sixteen vignettes describing a person with a depressive disorder or a psychotic disorder and answered a set of items measuring social distance.The person who was employed (vs. unemployed), or whose neighbors did not experience domestic noise disturbance (vs. disturbance) elicited significantly less social distance. Also persons with a depressive disorder elicited less social distance, vs. persons with a psychotic disorder.Employment and good housing circumstances may destigmatize persons coping with mental illnesses. Mental health and social services should encourage paid employment, quality housing and other paths to community integration. Stigma is a major concern for people living with a mental illness. The term stigma is applied when the following elements co-occur: (a) a distinction of labelling of human differences is made , (b) dominant cultural beliefs link labelled people to undesirable characteristics, (c) labelled people are placed in categories (‘them’ and not ‘us’), and (d) labelled people experience status loss and discrimination . FurtherInternational research shows that public stigma has an adverse impact on life opportunities of people with a mental illness. It is associated with diminished quality of life, social isolation, self-stigma, symptom exacerbation and relapse –7. FurthIn order to target and design interventions aimed at the reduction of stigma, it is important to know which living conditions and which characteristics of people with mental illness play a role in stigmatisation , 12. TheLess is known about which characteristics (other than psychiatric diagnosis) or living conditions of people with mental illnesses might affect the likelihood of public stigma. Perkins et al.  showed tNext to employment, we focus in this study on the themes youth and housing. Youth is of high importance since mental health problems and mental health stigma can emerge at a young age, and therefore consequences can be drastic . WhetherA focus on stigma regarding housing and communities is important, since inclusion of people with a mental illness in their communities contributes to social support, participation and recovery, and often stigma and exclusion emerges in the communities where people with a mental illness live –36. PeopFor this study, we translated the themes employment, youth and housing in characteristics of an individual with a mental illness in (a) being gainfully employed or not, (b) being younger or middle-aged and (c) being the source of domestic noise disturbance or not. Knowing more on social distance associated with such characteristics can serve as an input for developing or stimulating programs aiming at employment, youth and good quality housing, to further empower people with a mental illness. We chose to assess social distance as a measure for stigma because it is seen as one of the core components of stigma and a commonly used for the assessment of the concept , 43.An individual with a mental illness who is actively engaged in gainful employment will elicit less social distance than an individual with a mental illness that is unemployed;An individual with a mental illness whose neighbors experience no domestic noise disturbance will elicit less social distance than an individual with a mental illness whose neighbors do experience domestic noise disturbance;A young individual with a mental illness will elicit less social distance than a middle-aged individual with a mental illness;An individual with a depressive disorder will elicit less social distance than an individual with a psychotic disorder.An interaction effect for type of disorder on the one hand and unemployment, domestic noise disturbance and older age on the other hand is expected, with the latter characteristics having a stronger negative effect on social distance for a psychotic disorder.Our hypotheses are that:The study employed a cross-sectional, population-based design. Participants were Dutch citizens recruited from the CentERpanel, a panel set up in 1993 and maintained by CentERdata, which is a Dutch research institute specialized in data collection . The panIn January 2018, the 3209 active panel members received a questionnaire. One week after the initial questionnaire invitation, a reminder to complete the questionnaire was sent. One week later, data collection was closed. Respondents completed the questionnaire online, via a secured internet connection on their home computers. Eventually, 2388 panel members started and 12 of them did not complete the procedure, leaving 2376 (74%) questionnaires eligible for analyses. Mean age of the respondents was 54.6 (SD = 16.6), with a minimum of 16 and a maximum of 94 years old; 52% of the respondents were males.The online questionnaire contained one (from sixteen) randomly assigned vignette describing a fictional male  diagnosed with a mental illness and living in the community of a small-sized city. As a city we chose Nieuwegein, a typical Dutch city in the center of the country . To creAfter reading the vignette, respondents indicated on the Social Distance Scale (SDS) , 46 how To evaluate the effectiveness of the manipulation in the vignettes, respondents also evaluated Jeroen’s propensity for violence and contribution to his community on a five point scale, with 1 representing ‘very unlikely’ and 5 representing the answer ‘very likely’. It was expected that Jeroen causing domestic noise disturbance would be evaluated at being more prone to violence (compared to Jeroen not causing domestic noise disturbance), and Jeroen being unemployed would be seen as less likely to contribute to his community (compared to Jeroen being employed).In addition, respondents’ gender, level of contact with people with a mental illness, level of mental health literacy was assessed, and included as covariates in the analyses. Gender was assessed as a standard variable in the CentERpanel. Level of contact was assessed with the Level of Contact Report (LCR), containing seven levels, ranging from having ‘no contact’ with an individual with a mental illness to ‘I do (or did) have a mental illness myself’ , 48. MenBox 1Example of a vignette of Jeroen . Italics indicate text that differ for the levels of the four variables.a 40 year old man and lives in an apartment in Nieuwegein. After finishing school he started working as a logistic employee. After a few years he started to feel down, often for longer times. He had no appetite and lost quite some weight. His ability to concentrate on daily activities disappeared, as well as the energy to undertake any outings with his girlfriend. When he lost his job, he felt even more useless and he started suffering from a feeling of guilt and insomnia. Jeroen is often awake at night. Sometimes the neighbors complain about noise disturbance. A year ago his brother convinced him to seek help at a local mental health organization, where he was diagnosed with a depressive disorder. He has been taking medication ever since, next to group therapy. At this moment, Jeroen is unemployed and often visits the library to read some magazines.Jeroen is t tests were performed. Gender, level of contact (LCR) and mental health knowledge (MAKS) of the respondents were included as covariates, and their univariate associations with the outcome (the aggregated SDS-score) were analyzed with an one-way ANOVA and bivariate pearson correlations. To test the five hypotheses, a four-way ANOVA was performed, with age, employment, domestic noise disturbance and diagnosis as main effects. In addition, gender, the LCR and MAKS scores added as covariates in the four-way ANOVA.Descriptive statistics were analyzed with frequencies and means. For the evaluation the effectiveness of the manipulation in the vignettes, M = 2.58; SD = 0.88), compared to respondents that read the vignette in which Jeroen did not cause any disturbance  = 3.50, p < 0.01; d = 0.15). In addition, respondents that read the vignettes in which Jeroen was employed, saw him as being more likely to contribute to his community , compared to respondents that read the vignette in which Jeroen was not employed  = 22.40, p < 0.01; d = 0.91).Results of the manipulation check showed that respondents who read the vignettes in which Jeroen caused domestic noise disturbance, evaluated him as being more prone to violence towards others  = 2.50, p < 0.01]. As can be seen in Table Bivariate correlations between, and means, percentages (for different categories) and effect sizes of the covariates and study variables are shown in Table F5, 2360 =Mean SDS-score for all vignettes are shown in Fig. F = 47.65, p < 0.01, η2 = 0.020), domestic noise disturbance  and diagnosis  on the SDS-score. No main effect for age and no-interaction effects were found. Explained variance of the model was 5.1% (R2 = 0.051). Table R2 = 0.121).The four-way ANOVA without covariates, yielded main effects for employment , whereas the vignette in which Jeroen has a psychotic disorder, is unemployed, is associated with domestic noise disturbance and is 40 years of age, elicited the highest SDS-score . Translated to actual answers of respondents, this means that 33.3% percent of the respondents answered ‘no’ on the question ‘Would you like Jeroen to spend an evening socializing with you?’, for Jeroen, 40 years of age with a psychotic disorder, who is unemployed and is associated with domestic noise disturbance. Whereas 17.5% of the respondents answered similar for Jeroen with a depressive disorder, who is employed, is not associated with domestic noise disturbance and is 19 years old. For the willingness of Jeroen marrying into the family, the differences were sharper: 68.0% ‘no’ vs. 32.4% ‘no’ for the vignettes described above, respectively.Jeroen being employed elicited less social distance, as well as Jeroen not being associated with domestic noise disturbance and having a depressive disorder. The vignette in which Jeroen has a depressive disorder, is employed, is not associated with domestic noise disturbance and is 19 years old elicited the lowest SDS-score  without employment. Similar patterns were found in the study of Perkins , suggestStrength of the study is the high response on the questionnaire, resulting in a relatively accurate reflection of the Dutch-speaking population in the Netherlands and sufficient power to study subgroups or correct for other associations . Simultaneously, resulting in a disadvantage, this sample size also yields that even very small differences or effects reach significance very easily, as is the case in this study. Additional limitations of the study are the absence of a ‘control’ vignette: the situation in which the fictional persona has no mental illness. This prevents taking conclusions about an absolute effect of characteristics on stigma. Furthermore, we used the MAKS as an unidimensional scale for mental health knowledge. As indicated, the reliability of this scale was modest, and therefore results based on this use of the MAKS should be interpreted with caution. More research and attention to the use of the MAKS to assess mental health knowledge is warranted. Lastly, the reader should be aware that the variance explained by the model was a modest 12%, and effect sizes were (very) small. This means that offering additional, potentially destigmatizing information about people with mental illnesses only slightly alters someone’s perception. For the effect of noise disturbance the practical relevance is questionable since its effect neared 0%.Our results suggest that supporting clients in getting and keeping gainful employment can have a positive effect on the process of destigmatisation and social inclusion of people with a mental illness, by directly reducing the negative perceptions held by the general public. We also showed that this is independent of the diagnosis of the potentially stigmatized individual: it can be equally effective for people with diagnoses that differ in the strength of stigmatization. We also showed that this effect is independent of gender, level of contact and knowledge about the mental health of the general public.These findings underline the importance, added value and paradox-solving of methods like Individual Placement and Support (IPS), which is effective in helping people with severe mental illnesses to find competitive employment, and is implemented in many countries , 51, 52.As mentioned, the practical relevance of intervening in noise disturbance seems questionable given the small effect size in this study. However, the SDS contains just one question touching the topic of ‘living next door’. The other questions in the scale imply a closer contact, where the element of ‘noise disturbance’ is might be less relevant. This might have resulted in a relatively small opportunity to get the effect of noise disturbance expressed via a total score on the SDS. Further research should reveal if this remains the case. Additional implications for further research involve investigation of the generalizability of these findings toward other diagnoses, like drug or alcohol dependence. This is important, since in general—and in this study as well—the gradient of desired social distance follows ‘the more intimate the setting, the more likely the desired social distance’, but the gradient is not neat: for drug and alcohol dependence, ‘living next door’ produced a greater stigmatizing response than ‘friendship’ in social distance scale terms . Also, i