Amauroderma rugosum is an edible mushroom; however, its pharmacological properties have seldom been studied. Although the anti-inflammatory effect of the organic solvent extract of Amauroderma rugosum has been previously reported, it is not known whether the aqueous extract has a similar effect. In addition, the effect of Amauorderma rugosum extract on skin has never been explored. Therefore, the objectives of the present study were to evaluate the anti-inflammatory effects of the aqueous extract of Amauroderma rugosum on HaCaT keratinocytes, to explore its mechanisms of action, and to study the possible active ingredients involved. The results showed that the aqueous extract of Amauroderm rugosum at a concentration of 1.5 mg/mL was non-toxic to HaCaT cells and inhibited the release of cytokine interleukin-1β, and chemokines interleukin-8 and monocyte chemoattractant protein-1 in tumor necrosis factor (TNF)-α- and interferon (IFN)-γ-stimulated HaCaT cells. Amauroderma rugosum extract reduced the intracellular levels of reactive oxygen species. In addition, Amauroderma rugosum extract reduced the total protein expression of nuclear factor-kappa B (NF-κB) and B-cells inhibitor alpha in HaCaT keratinocytes and inhibited the phosphorylation of mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in TNF-α- and INF-γ-stimulated HaCaT keratinocytes. Chemical analysis revealed that the aqueous extract of Amauroderma rugosum contains polysaccharides, triterpenes, and phenolic compounds. Anti-inflammatory compounds, such as gallic acid, guanosine, and uridine, were also present. The anti-inflammatory effect of Amauroderma rugosum could be mimicked by a combination of gallic acid, guanosine, and uridine. In conclusion, our study suggests that the aqueous extract of Amauroderma rugosum exerts anti-inflammatory effects on keratinocytes through its antioxidant and inhibitory effects on MEK/ERK-, Akt/mTOR-, and NF-κB-dependent signaling pathways.Keratinocytes form the physical barrier of the skin and play an important role in the inflammatory process.  It is well-established that keratinocytes, which comprise 95% of the human epidermis, play an important role in the immune response of the skin. Upon stimulation by allergens and microbiological agents, keratinocytes express and release pro-inflammatory cytokines, chemokines, and adhesion molecules, which leads to skin inflammation through increased immunocyte infiltration at inflammatory sites . MoreoveAmauroderma rugosum (AR) is a basidiomycete belonging to the Ganodermataceae family. Although AR has not been widely studied, existing literature has reported its antioxidant and anti-inflammatory effects. Different extracts of AR have been shown to exhibit DPPH and ABTS scavenging activities in in vitro models [Ganoderma lucidum, which is the most common and widely studied mushroom in the Ganodermataceae family. One possible reason for this is the higher content of phenolic compounds in AR [o models ,4,5,6,7.o models ,4,8. In o models . Interesds in AR .In addition to its antioxidant and anti-inflammatory effects, AR also possesses anti-cancer, anti-hyperlipidemic, antibacterial, and neuroprotective effects . OrganicTotal polysaccharides, triterpenes, and phenolic compounds in the AR extract were measured using chemical assays. The content of total polysaccharides in AR extract was 44.23 ± 3.17  mg GE/g of dry weight. The content of total triterpenes was 5.89 ± 0.13  mg OAE/g of dry weight. The content of total phenolic compounds of AR extract was 6.82 ± 0.21 mg GAE/g of dry weight.The chemical constituents of the aqueous extract of AR were identified using mass spectrometry . The quaMTT assays showed that AR extract at concentrations lower than 1.5 mg/mL did not affect the viability of HaCaT keratinocytes . TherefoThe effects of AR extract on the pro-inflammatory cytokine IL-1β, and chemokines IL-8 and chemoattractant protein-1 (MCP-1) were evaluated. TNF-α/IFN-γ could increase IL-1β, IL-8, and MCP-1 release in HaCaT keratinocytes by 240%, 2372%, and 21,302%, respectively. AR extract itself had no effect on IL-8, IL-1β and MCP-1. However, 1.5 mg/mL AR extract significantly reduced TNF–α/IFN-γ-induced IL-1β release by 82%. AR extract (0.5 and 1.5 mg/mL) reduced TNF-α/IFN-γ-induced IL-8 release by 24% and 25%, respectively. AR extract (0.5 and 1.5 mg/mL) inhibited TNF-α/IFN-γ-induced MCP-1 release by 38% and 39%, respectively A–C.Further experiments were performed to determine the possible ingredients responsible for the anti-inflammatory effect of the AR extract. According to the results of chemical analysis, 1.5 g/mL of AR extract contained 10.7 ± 1.1 µM gallic acid, 6.1 ± 0.9 µM guanosine, and 6.9 ± 1.3 µM uridine. These concentrations of gallic acid, guanosine, and uridine showed a decrease in IL-1β release by 36%, 25%, and 23%, respectively, but failed to affect the release of MCP-1 D–F. UridAR extract itself had no effect on ROS generation, but the ROS level was elevated significantly by 429% after treatment with TNF-α/IFN-γ. The TNF-α/IFN-γ-induced ROS was reduced by 0.15, 0.5, and 1.5 mg/mL AR extract by 22%, 28%, and 46%, respectively .Several signal transduction pathways are involved in the inflammatory response of keratinocytes. Western blot analysis was performed to study the effects of the AR extract on inflammation-related signaling pathways. TNF-α/IFN-γ did not affect the expression levels of total mitogen-activated protein kinase (MAPK) kinase (MEK)1/2 and extracellular signal-regulated kinase (ERK)1/2 but could increase their phosphorylation levels by 158% and 156%, respectively. AR extract (1.5 mg/mL) did not affect the total and phosphorylated protein expression of MEK1/2 and ERK1/2, but 0.5 and 1.5 mg/mL AR extract reduced the TNF-α/IFN-γ-induced phosphorylation levels of MEK1/2 by 20% and 26%, respectively. Moreover, 1.5 mg/mL AR extract reduced the TNF-α/IFN-γ-induced phosphorylation of ERK1/2 by 34% .TNF-α/IFN-γ also did not affect the expression levels of total stress-responsive c-Jun N-terminal kinase (JNK) and p38 MAPK but increased their phosphorylation levels by 120% and 789%, respectively. AR extract (0.15 to 1.5 mg/mL) did not affect total and phosphorylated JNK and p38 MAPK protein levels. In addition, AR extract did not affect TNF-α/IFN-γ-induced phosphorylation of JNK and p38 MAPK .TNF-α/IFN-γ increased the expression levels of total nuclear factor-kappa B (NF-κB) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα) by 97% and 27%, respectively. TNF-α/IFN-γ also increased the phosphorylation levels of NF-κB and IκBα by 80% and 70%, respectively. AR extract (1.5 mg/mL) alone did not affect the total and phosphorylated protein levels of NF-κB or IκBα. However, 1.5 mg/mL AR extract reduced the TNF-α/INF-γ-induced total protein levels of NF-κB by 23%, and 0.5 and 1.5 mg/mL AR extract inhibited TNF-α/INF-γ-induced total protein levels of IκBα by 19% and 33%, respectively. Nonetheless, AR extract did not affect TNF-α/INF-γ-induced phosphorylation of NF-κB or IκBα .Lastly, TNF-α/IFN-γ slightly decreased the expression levels of protein kinase B (Akt) by 27%, but it had no effect on the mammalian target of rapamycin (mTOR). TNF-α/IFN-γ increased the phosphorylation levels of Akt and mTOR by 186% and 101%, respectively. AR extract (0.15 to 1.5 mg/mL) alone had no effect on total and phosphorylated protein levels of Akt and mTOR, but AR extract (1.5 mg/mL) reduced the TNF-α/IFN-γ-induced phosphorylation levels of Akt and mTOR by 46% and 28%, respectively .Drug-likeness of gallic acid, guanosine, and uridine, which might be the potential active ingredients of AR extract, was evaluated using Molsoft scheme . The druIt has been suggested that AR possesses anti-inflammatory properties. In Asian countries, such as China, AR is used as a medicinal herb for the treatment of acute or chronic nephritis . MoreoveIL-1β and IL-6 are the most well-known cytokines that mediate inflammatory cell migration, keratinocyte proliferation, and production of additional cytokines by keratinocytes . TherefoTNF-α/IFN-γ activates several intracellular signaling pathways in keratinocytes, including those related to mitogen-activated protein kinases (MAPK) in HaCaT cells . There a3K-Akt-mTOR signaling pathway plays a crucial role in the normal cutaneous healing process, and rates of wound healing are directly dependent on the sustained activation of this pathway [NF-κB, a downstream molecule of MAPK, regulates the expression of genes, enzymes, and adhesion molecules involved in chronic inflammatory diseases . In the  pathway . In our 2+ radicals [Oxidative stress is a key factor contributing to inflammatory disorders. ROS can activate NF-κB, which regulates genes such as TNF-α, interleukins, and inducible nitric oxide synthase (iNOS) . In guinradicals ,7. Apartradicals .Ganoderma lucidum [Ganoderma lucidum in protecting cardiomyocytes from DOX-induced oxidative stress [The total content of polysaccharide, triterpene, and phenolic compound in the aqueous extract of AR were measured in our study. Our previous study also reported that the content of total phenolic compounds in the aqueous AR extract was higher than that in the aqueous extract of  lucidum . This mae stress . Accordie stress ,31,32. Me stress . In a moe stress . In the e stress . The effIn addition to gallic acid, the aqueous extract of AR also contained nucleosides such as guanosine and uridine, which are known to possess anti-inflammatory properties. For instance, uridine reduced oedema and infiltration of leukocytes in the bronchoalveolar lavage fluid in an animal model of lung inflammation ,36. MoreAccording to the results of our chemical analysis, 5 µM guanosine and uridine were found in 1.5 mg/mL of the AR extract. However, this concentration of guanosine or uridine only reduced IL-1β and IL-8 release but did not affect the release of MCP-1 in HaCaT keratinocytes. Therefore, similar to gallic acid, guanosine or uridine alone did not contribute to the anti-inflammatory effect of AR extract on HaCaT cells. Interestingly, the combination of gallic acid, guanosine, and uridine could inhibit the release of IL-1β, IL-8 and MCP-1 in HaCaT cells. Nevertheless, the effect of combination of gallic acid, guanosine and uridine on IL-8 release was higher than that of AR extract. It clearly indicated that other active ingredients may be present and able to inhibit IL-8 release. In contrast, the effects of combination of gallic acid, guanosine and uridine on IL-1β and MCP-1 release were lower than that of AR extract. The reason is not known. Further investigation is required to verify if there are some compounds in AR extract that may trigger IL-1β and MCP-1 release.As mentioned above, we cannot exclude the possibility that other compounds present in the aqueous extract of AR  may alsoTopical corticosteroids are still the mainstay of treatment for inflammatory skin diseases, such as atopic dermatitis . HoweverRPMI 1640 medium, penicillin-streptomycin, 0.25% trypsin, fetal bovine serum, human TNF-α recombinant protein, and CM-H2DCFDA were purchased from Invitrogen . RIPA Lysis and Extraction Buffer, Halt™ Protease Inhibitor Cocktail, and BCA Protein Assay Kit were purchased from Thermo Fisher Scientific . Gallic acid, guanosine, uridine, thiazolyl blue tetrazolium bromide (MTT), dimethyl sulfoxide (DMSO), and phenylmethylsulfonyl fluoride (PMSF) were purchased from Sigma-Aldrich . The human CXCL8/IL-8 DuoSet ELISA, human CCL2/MCP-1 DuoSet ELISA, human IL-1β/IL-1 F2 Duoset ELISA, and human IFN-γ recombinant protein were purchased from R & D Systems . All the antibodies used for Western blotting were purchased from Cell Signaling Technology . ECL Select Western blotting detection reagents were purchased from GE Healthcare Life Sciences .g for 10 min. The supernatant was then collected. The undissolved residue was boiled in water twice, and all the extracted residues were pooled, filtered, and condensed to 80 mL using a rotavap. The extract was stored at −20 °C. The extract was filtered through membrane filters with pore size of 0.22 µm before experiments.AR was provided by Hong Kong Ganoderma Centre Limited . The fruiting bodies of the AR were dried and powdered. Two grams of AR powder were boiled in 50 mL distilled water for an hour. The extract was then centrifuged at 4000× The total polysaccharide, triterpene, and phenolic compounds were analyzed by chemical assays, as reported by us previously . GlucosThe compounds in the AR extract were identified using ultra-performance liquid chromatography (UPLC) Q-Exactive Orbitrap tandem mass spectrometry (MS)  fitted with an electrospray ionization source. The following experimental parameters were adopted: ion spray voltage, 3.5 kV; capillary temperature, 320 °C; sheath gas flow rate, 35 Arb; heater temperature, 350 °C; auxiliary gas flow rate, 10 Arb. Data were collected for both positive and negative ions with a mass scanning range of 50–1500 m/z. Data were processed and analyzed using Xcalibur™ version 2.2.1 and Trace Finder 3.3 version (Thermo Fisher Scientific Inc.) along with compound discoverer software .18 column . The mobile phase A contained 0.1% formic acid (v/v) in water and mobile phase B contained and 0.1% formic acid (v/v) in acetonitrile. The flow rate was 0.30 mL/min, and the injection volume was 2 µL. The gradient elution processes were 0–45 min, 5–95% B; 45–55 min, 95% B. UV-visible spectra were recorded in the range of 190–400 nm. Different reference standards were used according to the results of UPLC Q-Exactive Orbitrap tandem MS.A Dionex UltiMate 3000 Rapid Separation UPLC system (Thermo Fisher Scientific Inc.) equipped with a DAD-3000RS detector was used for the quantitative analysis. The chromatographic separation was carried out at 30 °C on a SunFire C2.HaCaT keratinocytes were purchased from AddexBio . The cells were cultured in RPMI medium supplemented with 8% heat-inactivated FBS, 1% penicillin-streptomycin, and cultured at 37 °C in an incubator with a humidified atmosphere of 5% COHaCaT cells were treated with AR extract (0–1.5 mg/mL) in the presence of 10 ng/mL recombinant human TNF-α and 10 ng/mL IFN-γ for 24 h. Inflammatory responses, reactive oxygen species levels, and signaling pathways were studied.To study the toxicity of AR extract in HaCaT cells, cell viability was assessed using the MTT assay. After the drug treatment, the cells were incubated with 0.4 mg/mL MTT for 3 h at 37 °C. DMSO was then added to lyse the cells and dissolve the purple formazan crystals formed inside the cells. Absorbance was measured using a microplate reader at 560 nm.g at 4 °C for 10 min to remove the cell debris. Interleukin (IL)-1β, IL-8, and monocyte chemoattractant protein (MCP)-1 in the supernatants were detected using the human IL-1β/IL-1 F2 Duoset ELISA, human CXCL8/IL-8 DuoSet ELISA, and human CCL2/MCP-1 DuoSet ELISA, respectively, according to the manufacturer’s instructions.After the treatment with AR extract, the culture media were collected and centrifuged at 5000× The cells were then washed with PBS and stained with 2 µM CM-H2DCFDA for 15 min. After thorough washing with PBS to remove the unbound dyes, the cells were detached from the culture plate using 0.25% trypsin. The green fluorescent signal of CM-H2DCFDA was examined via flow cytometry using the FITC channel.g at 4 °C for 10 min. The supernatant was then collected. To determine the total protein concentration of each sample, BCA assay was performed according to the manufacturer’s instructions. Equal amounts of protein samples were loaded onto 8–10% SDS gel for electrophoresis and then electrotransferred to PVDF membranes. The membranes were blocked with 5% non-fat milk for 1 h at room temperature and then incubated with primary antibodies against ERK1/2, phospho-ERK1/2 (Thr202/Tyr204), MEK1/2, phospho-MEK1/2 (Ser217/221), JNK, phospho-JNK (Tyr183/Tyr185), p38, phospho-p38 (Thr180/Tyr182), NF-κB p65, phospho-NF-κB p65 (Ser536), Akt, phospho-Akt (Ser473), mTOR, phospho-mTOR (Ser2448), or GAPDH (1:1000 dilution in 5% BSA in TBS) at 4 °C overnight. After washing thrice with TBS containing 0.1% Tween-20 (TBST), the membrane was subjected to horseradish peroxidase-conjugated secondary antibody (1:2500 dilution in 5% BSA in TBS) for 1 h at room temperature. The membrane was washed again with TBST and visualized using ECL Select Western blotting Detection Reagents with a ChemiDoc XRS Molecular Imager .Protein of HaCaT keratinocytes were extracted using RIPA lysis buffer containing 1% PMSF and 1% Halt™ Protease Inhibitor cocktail. The cell lysate was centrifuged at 13,000× http://molsoft.com/mprop/ accessed on 25 September 2022) was used for quantifying the drug-likeness of compounds. Based on various molecular properties, including the number of hydrogen bond acceptor (HBA), number of hydrogen bond donor (HBD), molecular weight, water partition coefficient (MolLogP), water solubility (MolLogS), molecular polar surface area (MolPSA), molecular polar surface volume (MolVol), acid dissociation constant (pKa), and blood–brain barrier (BBB) score, the software quantified a value known as “Molsoft Score”, which determines the drug-likeness of compounds.Molsoft  was used to calculate statistical significance within groups. Statistical significance was set at In summary, our study demonstrated that the aqueous extract of AR exerts anti-inflammatory effects on HaCaT keratinocytes, probably through its antioxidant effect and the inhibition of MEK/ERK, Akt/mTOR, and NF-κβ signaling pathways. Our results also showed that the aqueous extract of AR contains gallic acid, guanosine, and uridine. They may be part of the active ingredients responsible for the anti-inflammatory effects of AR, although the presence of other active ingredients cannot be excluded. Further studies using animal models and clinical trials are required to confirm the potential application of AR in treating inflammatory skin diseases.


In the past 20 years, a vast amount of research has shown that Augmented and Mixed Reality applications can support physical exercises in medical rehabilitation. In this paper, we contribute a taxonomy, providing an overview of the current state of research in this area. It is based on a comprehensive literature review conducted on the five databases Web of Science, ScienceDirect, PubMed, IEEE Xplore, and ACM up to July 2021. Out of 776 identified references, a final selection was made of 91 papers discussing the usage of visual stimuli delivered by AR/MR or similar technology to enhance the performance of physical exercises in medical rehabilitation. The taxonomy bridges the gap between a medical perspective  and the Interaction Design, focusing on Output Technologies and Visual Guidance. Most approaches aim to improve autonomy in the absence of a therapist and increase motivation to improve adherence. Technology is still focused on screen-based approaches, while the deeper analysis of Visual Guidance revealed 13 distinct, reoccurring abstract types of elements. Based on the analysis, implications and research opportunities are presented to guide future work. The three kinds of therapy are mostly used for similar clinical pictures, such as physical damage and disabilities due to illness or accidents. The spectrum ranges from damage to the spine and joints to diseases of the central nervous system or the effects of a stroke. Expanding on the latter, according to the World Health Organization (WHO), strokes are not only often fatal but also the third leading cause of disability worldwide [As people age, serious illnesses and injuries requiring medical rehabilitation become more common . The demorldwide , reducinorldwide . Patientorldwide , requiriorldwide ,7,8. TheConventionally, specialized prevention and rehabilitation facilities provide in-clinic physical therapy which is quite demanding in terms of time and cost, requiring supervision as well as individual treatment plans and modifications as per the patient’s progress . SimultaA vast amount of research has aimed to employ and adapt technology to support the rehabilitation process and overcome these problems. In particular, different implementations of Augmented and Mixed Reality (AR/MR) technologies have been applied and, as we will outline in more detail in this paper, these show that such approaches might indeed help to support the rehabilitation process. The advantage of AR/MR is that it allows merging visual digital cues with the real environment of the patient, thus letting the user focus on the physical task or exercise while still providing visual guidance in a digital form which is anchored to the real world to provide context. In their systematic literature review, Cavalcanti et al. approach the relationship between Augmented Reality and motor rehabilitation from a different angle . They anThe current literature, as will be outlined in examples later, sheds light on significant aspects of visual elements that have helped patients to benefit more in the rehabilitation process utilizing this technology and can be investigated further. For example, different forms of instructions or feedback delivered by visual cues  and sometimes accompanied by audio can be utilized to communicate the correct movements and thereby enable the patient to perform the exercises correctly . BesidesVisual Guidance aimed to help patients in their rehabilitation, for example, by allowing them to perform exercises autonomously at home without any supervision by a therapist;Identifies different forms of AR/MR Technologies used for visual output in the field of physical rehabilitation;Provides an overview of the current use of the variety of Patient Types, Medical Purposes, Technologies, and specific Visual Guidance approaches used to support the patient in their rehabilitation process.Derives insights regarding the relations between Due to these potentially beneficial properties of AR/MR in the context of physical rehabilitation and the vast amount of existing work in this area, we identified the need for a comprehensive literature review. From the perspective of HCI, it also seems necessary to address the in-depth examination of visual guidance that can benefit HCI researchers or practitioners in the long run. The categorization will not only help to provide a better understanding of the visual guidance elements used in the rehab applications but will also uncover interesting insights and identify research gaps. Thus, this paper aims at providing a taxonomy which:To gain a thorough understanding of the different AR/MR visual guidances that assist patients in the rehabilitation process, the relevant literature was retrieved from different databases, containing a mixture of medical and HCI literature. For the chosen research question, we decided to perform the literature review in the form of a scoping review. Unlike systematic reviews, scoping reviews aim to address broader topics and sources employing different methods and study designs, while focusing less on narrow questions nor the assessment of quality. They are most useful for providing an overview of the extent, range, and nature of currently evolving areas of research, to summarize research findings or to identify research gaps ,17. In oThe analysis process was initialized with a prescreening focusing on the abstract of a paper, followed by a full-text assessment for a relevant subset. On the resulting set of references, we applied an open-coding scheme, meaning that relevant categories and codes were not predefined but identified based on the screening results and adjusted through the thorough analysis of the reviewed studies. This way, a meaningful segmentation could be derived in relation to the research question. Three main and eight subcategories evolved during the coding process and were subsequently applied to the whole data-set. Codes within a category were not mutually exclusive. The classification of the final set of papers along the coding scheme was carried out by the first three coauthors of this review. As with the selection process, each application was reviewed by two researchers. Discrepancies were resolved in discussion with the third reviewer. A detailed description regarding the eligibility criteria and study selection process is explained below.physical rehabilitation.The performance of physical exercises in medical rehabilitation. As mentioned above in the introduction, medical rehabilitation consists of a variety of treatment methods, including the fields of physiotherapy, occupational therapy, and physical therapy . As thesThe output technologies Augmented and Mixed Reality (AR/MR) as means to support the different types of physical exercises. The available vast amount of research in combination with the potential that future developments of the technology offer, we think, merits such a rather strict technological focus of this literature review. As has been the approach by other researchers , we wilThe actual use of visual stimuli or visual guidance to support patients during the rehabilitation task. Here, we did not limit our review to graphical stimuli but included representations with text as well.As motivated in the introduction, our main focus is on the following items:We based our review on the following five databases: Web of Science, ScienceDirect, PubMed, IEEE Xplore, and ACM. This diverse focus is necessary considering the multidisciplinary nature of the research question, connecting information technology, especially the area of human–computer interaction, with the field of medical rehabilitation. Web of Science and ScienceDirect offers such a broad, multidisciplinary overview of the scientific spectrum. PubMed is the leading database within the medical field, including research on physical therapy from both the patients’ and therapists’ viewpoints. IEEE Xplore and ACM, on the other hand provide a stronger technological perspective.Physical Therapy”, “Physiotherapy”, “Physical exercise”, “Physical rehabilitation”, “Occupational Therapy”, “Stroke rehabilitation”.The research must take place in the context of physical rehabilitation, i.e., physical exercises in medical rehabilitation. Therefore, at least one of the following search terms had to be included in the title, keywords, or abstract: “Mixed Reality”, “Extended Reality”, “Augmented Reality”, “Visual Cues”, “Visualization”, “Visualisation”, “Video-based”.Furthermore, the research must use some kind of AR-/MR-based visual guidance or stimuli to support the patient in their rehabilitation. Consequently, one of these search terms must be found in the title, keywords, or abstract in addition to the first requirement: “We chose search terms in accordance with the research question and iteratively expanded them based on the keywords of relevant references found. To be shortlisted in the database search, the following two requirements had to be met:Early database searches in the field of medical rehabilitation emphasized the importance of research aimed at the rehabilitation of stroke patients, resulting in an explicit mention of this condition in the keywords. In addition, the search did not require AR/MR terms but also allowed papers to be examined which used some kind of visual guidance.We included original articles, conference papers, and demonstrations in the search, as well as literature reviews, as these may reference interesting papers otherwise not found in the search. In order to illustrate both the progression and the state of the art of research in the highlighted area, no restrictions were placed on publication year. Due to the terms chosen, the focus of the search was on English publications but encountered references in other languages were translated and considered as well. The last search took place on the 27 July 2021.The reference addresses physical exercises in medical rehabilitation, but without the use of AR/MR-based or comparable visual guidance or support for the patient (104).The reference addresses medical rehabilitation but not physical exercise (38).The reference addresses the use of visual support in medical education or training, aimed at the medical professional (29).The reference uses no distinct visualization, but instead either considers the feasibility of conventional rehabilitation delivered via video calls or the effect of commercially available mobile games on general activity (17).The reference explicitly considers psychotherapy or psychiatry without physical exercise (15).The reference addresses other medical fields, such as medical imaging or surgery (125).The reference is off-topic in other ways, for example, including other data visualization in Machine Learning, Artificial Intelligence, Veterinary Sciences, applications not employing AR/MR or VR, and game reviews (67).A total of 776 references were found. An overview of the selection process is depicted in The references utilize no or an insufficient level of visualization (14).The references mention a system using visualization but do not explain it in enough detail, which would help other researchers and practitioners to build upon their results (13).The references utilize a system or application which was already (and better) explained in another paper included in the data-set. This took place many times as research groups would commonly deploy a single application for a number of distinct papers, such as a preliminary report, a feasibility study, a paper explaining the technical development, and a clinical long-term study (33).The references are literature reviews showing no distinct visualization, but refer to other potentially interesting papers (9).The references are off-topic in other ways (5).In addition, one single reference could not be procured (1).This resulted in 164 references which were assessed in more detail, i.e., via a full-text analysis, employing the same dual control principle mentioned before. Another 80 references were excluded in this step for the reasons stated below:This assessment left 84 studies to be included in the review. Despite our focus on AR/MR technology, we did not exclude papers employing Virtual Reality, as long as they fit our search terms, explored the use of visualization to support patients within the field of physical rehabilitation, and sufficiently explained their visualization. Additionally to the initial search, we screened the references cited by the set of 164 in-depth assessed papers and identified 7 further references which we included as well. This led to a final set of 91 references which were examined in the following. The publication years of the considered papers range from 2002 to current releases.Among the 91 references, some include two or more diverse approaches or applications, such as for means of comparison, for distinct tasks of different body parts, or to allow the user to choose out of a set. In cases where there was a clear distinction between applications, all were considered individually in our review. However, very similar applications, such as slightly modified pick-and-place-tasks, within a single reference were treated as one. As a result, we identified 114 distinct applications, which form the basis of our taxonomy. An overview of the 114 applications, structured by reference and the coding scheme of the taxonomy, is provided in the Patient Types, which could further be separated in different Medical Conditions as well as Affected Body Parts. While these may not be mutually exclusive from a medical point of view, not all references provided the necessary medical details and rigor, which made us opt for such a rather practical separation.Firstly, we identified as the main category, that the 114 applications focused on different Medical Conditions considered in the references were of Neurological nature , predominantly Stroke  with only few mentions of other conditions such as Parkinson . Further, interventions following Injury or Surgery  were considered as well. Finally, a set of Other  with either unspecific or diverse conditions was identified. For example, we found a single study examining neck pain [The most prevalent eck pain  as well eck pain .Affected Body Parts, 81 (71%) of the applications especially aimed at Upper Limb, out of which 52 (46%) were focused on the Hands, Fingers, or Wrist, 20 (18%) on the Shoulder, and 21 (18%) on the Elbow. A total of 33 (29%) applications considered the Lower Limb, while only 4 (4%) of these further emphasized either the Knee or Ankle. Another three (3%) applications regarded Other parts of the body, namely the neck once [Regarding the eck once ,24.Medical Purpose, covering the reasoning behind the different applications from a medical perspective. We further subdivided this category into Bodily Functions and Added Value.Secondly, we identified the main category Bodily Function describes the primary, functional purpose of the physical rehabilitation. Four types of functions were identified. In total, 96 (84%) of the applications were aimed at restoring or improving Motor Functions of certain joints or limbs. A further 26 (23%) aimed to improve Gait or Balance, while 24 (21%) aimed at building Strength. Only 13 (11%) applications explicitly addressed the enhancement of Cognitive Skills.The Added Value captures the benefits that researchers aim to achieve through the means of technology used in the applications, and thereby go beyond what conventional physical therapy provides. Most of the applications aim to provide several such benefits. The most common added value is an increase in Autonomy, allowing patients to perform the exercise without close supervision by a therapist, which applies to 91 (80%) of the applications. An additional goal is to overcome the repetitive and boring nature of many therapeutic exercises by increasing the motivation of patients. Here, two aspects play a role. First, 87 (76%) applications aim to improve patients’ Adherence, meaning their likeliness to continue with their rehabilitation program over a prolonged period, while 47 (41%) aim at boosting their Effort during a session. Motivational factor is considered by 75 (66%) of applications, which assist the patient during an exercise by providing real-time Performance Feedback, whereas 46 (40%) allow for an Analysis of the performance after the session. Among all, a noteworthy added value, which a technological solution may provide, is an increase in patients’ Accuracy to perform the exercises, which is considered by 39 (34%) of the identified applications.The Interaction Design, revolves around the technical solutions as implemented in the different applications. It, therefore, comprises the used Output Technology, the Application Type, the concrete kind of Visual Guidance employed to aid the patient, as well as the Input Technology required for the AR/MR technology to work.The third and the last main category, Output Technology, 72 (63%) of the applications could be considered screen-based, i.e., making use of a type of 2D display, mobile phone, or projector image to superimpose digital content on video-based real-world imagery. Only 8 (7%) of these applied a handheld Mobile Phone-based AR/MR approach, similar to Pokémon Go and the like. Another 30 (26%) of the applications used a Head-Mounted Display (HMD), out of which 13 (11%) used a VR HMD and 17 (15%) an AR/MR HMD. Another 14 (12%) of the applications delivered the application via a Spatial-AR/MR approach, which uses a projector to display digital content onto the patient and his surroundings, thereby registering the virtual content in 2D space [As for the 2D space .Application Type can be either Game-based, signifying playful and fun solutions employing gamification elements, as 55 (48%) of the applications were, or Task-based, as were 53 (46%). Compared to their game-based counterpart, Task-based applications emphasize a more serious approach, focusing on the execution of simple, repetitive exercises rather than motivational aspects. As another item in this category, we extracted Mirror Therapy as a highly specific type found in 12 (11%) of the applications. In mirror therapy, the brain is tricked into thinking that an affected limb, for example, an amputated arm, is able to move without pain. This is achieved through putting a mirror in a specific spatial configuration next to the healthy arm. The brain now connects the mirrored image with the affected limb, so that when the patient tries to move both arms , it assumes that also the affected limb is moving correctly, helping to train the relevant function and mitigate pain [The ate pain .Visual Guidance elements. In total, 13 reoccurring abstract concepts were found here, which we classified into three groups: Guided Interaction, Demonstrated Interaction, and Feedback. The concepts are explained in the following.The main emphasis of our analysis lays in the identification of the Guided Interaction includes such visual support elements, aiding the patient by demanding immediate interplay. We identified the following elements:Target: A total of 64 (56%) of the applications use some form of Target, which we define as a spatial destination to be reached by the patient. For example, in Garcia and Navarro [ Navarro , the use Navarro  shows raPath: Related to targets are Paths, which not only show the destination but also a trajectory to be followed. Compared to targets, paths provide information during the entire execution of the exercise. In total, 21 (18%) of the applications use this type of visualization. In SleeveAR [SleeveAR , a path SleeveAR  visualizDirection: Overall, 15 (13%) applications do not show an entire path but indicate a Direction to be followed instead, usually visualized by an arrow. In the ARDance game [nce game , the usence game  uses a snce game  also visObject: The most common element is Objects, found in 69 (61%) of the analyzed applications. Objects, unlike targets, can be interacted with in some way. For example, in the Ocean Catch Game by Park et al. [k et al. , the usek et al. , which rRacket/Cursor: A Racket or Cursor is an object directly controlled by the patient which allows them to manipulate other objects; 21 (18%) of the analyzed solutions utilize such a racket. For example, with the help of a marker, the bar is used to hit the ball in a game of Pong as shown by Dinevan et al. [n et al. . FruitNin et al.  shows a Obstacle:Obstacles describes hindrances to be avoided or bypassed. They are employed in 11 (10%) of the applications. To facilitate practicing gait and balance exercises, the obstacles can be projected directly onto the treadmill [readmill   of the analyzed applications. For instance, UNICARE Home+ by Yeo et al. [o et al.  shows a o et al.  uses theVirtual Coach: Unlike with an unchanging recording, a Virtual Coach provides interaction with the user. Such a coach was used in seven (6%) of the analyzed solutions. The holographic representation of a virtual coach as depicted in Mostajeran et al. [n et al.  allows uOverlay: An Overlay displays a visual instruction directly perceived on the user’s body. In total, 15 (13%) applications employed such an Overlay. In a Kinect-based system as shown by Pachoulakis et al. [s et al. , the useFeedback. These elements guide the patient indirectly by adding another layer of information related to the task or exercise. Often, these elements inform the patient about the quality of their performance.The last group of visual guidance contains elements providing Text: In total, 23 (20%) applications deliver Text-Based Instructions or Feedback. ARKanoidAR [KanoidAR  uses texKanoidAR  motivateScore/Graph: A total of 60 (53%) of the analyzed solutions provide the patients with some kind of informative Graph, Score or Progress Bar related to their performance. When the task is performed correctly, the score is increased, as depicted in FruitNinja [uitNinja  or ARKanuitNinja  games. SColor-code: Information can also be transported using a Color-Code which is used by 23 (20%) applications. To illustrate if the user has reached the target appropriately, interACTION [erACTION  uses a cerACTION  is to coSelf-Evaluation: Altogether, 26 (23%) applications grant the patient some kind of improved Self-Evaluation delivered by either another camera angle or mirror to visualize the real affected body part better as shown in Physio@Home [sio@Home   applications. Examples include the work of [Marker-based Motion Tracking, which is utilized by 38 (34%) solutions. Few prototypes such as Physio@Home [Sensor-based Motion Tracking such as Xsens used by [Haptic Device to simulate tactile sensation in AR environment when users touch virtual objects as used by [Additional Device, such as a treadmill used by [Lastly, the  work of ,43 that  work of . Moreovesio@Home  and gaitsio@Home  used Vic used by . Nine  of the references. Similarly yet less pronounced is the accentuated focus of the Upper Limbs compared to the Lower Limb, with 81 (71%) compared to 33 (29%) references. Distinct differences become apparent between research in these areas. These findings coincide with those of Cavalanti et al. who, in their literature review of studies employing AR in rehabilitation, found a strong prevalence of Upper Limb research and a severe yet less pronounced focus on Stroke [As became apparent during the open coding process, a large majority (73%) of the identified references explicitly focus on rehabilitation following Upper Limb are predominately focusing on individual parts of the limb, sometimes multiple, as seen in Upper Limb, 51 (63%) target either the Hand, Fingers or Wrist, 21 (26%) the Elbow and 20 (25%) the Shoulder, leaving only 19 (23%) references without a specific focus. In contrast, the 33 references regarding Lower Limb are overwhelmingly nonspecific (79%) with only 7 applications (21%) focusing on either the Knee, Ankle or both.First, studies aimed at Bodily Functions depending on the considered Body Part. 79 (98%) out of the 81 Upper Body applications target the restoration or improvement of specific Motor Functions, while 19 (23%) aim to increase the patient’s muscle Strength. In comparison, with 24 (73%) the largest fraction of the 33 Lower Limb research addresses the patient’s Gait or Balance, especially in order to prevent future falls. Improvement of Specific Motor Function, however, is only targeted in 19 (58%) references here. Muscle Strength is also considered less often, finding explicit mentioning in five (15%) of the references.Further, there is a difference in the targeted Lower Limb and Gait has increased immensely in recent years, as illustrated in Lower Limb, representing only 18% of the research papers published in this time frame. Further, only eight of these (62%) aim at Gait or Balance. Compared to that, 20 out of 43 applications published since 2019 target Lower Limb (47%). Additionally, the share of Lower Limb research focusing Gait or Balance rose to 80%.Lastly, the research focused on both Application Type and their relation with Medical Purpose:Bodily Functions, 11 out of the 13 (85%) applications aiming to provide Cognitive training do so by employing Game elements.Regarding the Game-based applications are especially often used to increase the patients’ motivation, with 51 (93%) of them targeting increased Adherence. For the 53 Task-based applications, Adherence is a much less prominent goal, which is only addressed by 31 (58%) applications. In total, 30 (55%) of the Game-based applications further aim to increase the patients’ Effort during the session, compared to only 16 (30%) within the set of Task-based approaches.The 55 Task-based applications focus on increased Accuracy, compared to only 11 (20%) within the set of Game-based applications.Instead, 28 (53%) Differences become apparent between the variants of Visual Guidance elements by Application Type and targeted Added Value. The main insights are summarized below.Task-based applications are more balanced in their use of visual elements, while Game-based are more focused on certain elements, namely Objects (91%), Scores or Graphs (80%), and Targets (65%).In general, Game-based applications are from the Guided Interaction group. Elements from this group are used in 53 Game-based applications (96%) and make up 59% of all elements used here. In comparison, they are used in 38 Task-based applications (72%) and account for 46% of elements used.The most common visual elements implemented in Game-based applications (16%) utilize one form of Demonstrated Interaction each, accounting for 4% of elements. Within Task-based applications, 24 (47%) employ at least one Demonstrated Interaction element, accounting for 19% of all elements.In contrast, only nine Interaction Design approaches and in particular discuss different approaches and implications within the categories Visual Guidance and Output Technology.In this section, we will take a closer look into the Guided Interaction elements, such as Targets, Objects, Paths, and Racket/Cursor. The game required no controllers or sensors to operate. The main challenge the authors reported was to keep the game engaging, which they tried to tackle by providing higher difficulty levels. Alamri et al. found that virtual Objects, such as a cup in their Shelf Exercise approach [HMD-AR/MR or Spatial-AR/MR and the authors conclude that these can enhance the user experience along with increasing patients’ participation in the rehabilitation program. For applications aiming to improve gait adaptability, Fonteyn et al. and subsequently Timmermans et al. were able to show that Guided Interaction involving the element of Obstacles, i.e., avoiding/dodging hindrances, can indeed improve gait performance [Garcia and Navarro were able to show that the MobileReh  app enhaapproach , tend toformance ,47.Spatial-AR and Screen-based category, respectively. The authors observed that the Spatial-AR mode provided better hand-eye coordination which plays a significant role in completing tasks. The Objects were projected directly on the tabletop that made it easier for users to interact. Compared to this, in the Screen-based mode, where the output was displayed on a monitor, visual and proprioceptive feedback were uncoupled because the gaze was directed on the monitor and not their hand, resulting in poor motor performance.Seyedebrahimi et al. conducted a study to compare different implementations of the FruitNinja game . They coGuided Interaction vs. Demonstration and Virtual Coach: Several researchers compared their Guided Interaction approaches to Video Demonstration. For example, Sousa et al. found that the movement Path as shown in SleeveAR [Video Demonstration alone. The Path not only guided the user on how to move but drawing the trajectories over the original exercises helped understanding the areas of improvement. In a similar manner, Tang et al. performed an experiment to investigate if the wedge visualization , as shown in Physio@Home [Video Demonstration. It was shown that the movement Path guided users better to perform the steps correctly for hand exercise. However, for elbow exercise, the results were not any better than Video Demonstration due to a technical limitation. Overall, the corrective guides helped people to realign themselves when needed. In their work, Sodhi et al. explored on-body projected hints (Overlay). In their approach LightGuide [Video Demonstration. It was reported that Video Demonstration is unable to adequately show next steps. In comparison, visual hints such as a 3D Arrow helped users to exercise at their own tempo and guided them to perform the movement in a particular direction. 3D Pathlet on the other hand served as a feedforward component to guide the user in advance what is ahead in the Path. The question is still open if such visual hints on a Screen will allow users to perform the movement as accurately as when they are projected on to the body.SleeveAR  showed bsio@Home , helped ghtGuide , this heDemonstrated Interaction mostly chose Video Recordings, other researchers have explored Virtual Coaches as a digital representation or surrogate for a real therapist. Mostejarean et al. [Virtual Coaches in the form of holographic representations have potential to help older adults in Balance training. Results suggest that a Virtual Coach was well perceived by the users and the holographic representation of the Virtual Coach made it easier to look at it from different perspectives-something that is difficult to achieve with Screen-based systems. The Virtual Coach was able to interact with users with the help of audio and speech feedback. Users reported that the visual representation of the avatar should be more human-like to make it feel real and alive. The authors conclude that such a personalized coaching system has the potential to be used in home-based therapy setting. Another form of Virtual Coach was used by Han et al. [Overlaid the Virtual Coach’s guided bone structure onto the user’s body to perform Tai-Chi maneuvers recorded by a motion capture system. The participants reported that they were able to perform tasks well using this immersive technique and better compared to simple instructions by pictures or words.While these comparisons with n et al.  conducten et al. . They OvFeedback: Another approach to address gait performance was investigated, for example, by Liu et al, focusing on avatar-based feedback [Self-Evaluate the movements of the user. They showed that the availability of multiple views of an avatar allows different perceptions, depending on the current users’ need which makes it quite versatile in nature. Additionally, it also provided unique concurrent information on walking performance and was able to show improvements compared to communicating such information directly by clinicians or therapists. Bell et al. evaluated the real-time visual Feedback in their interACTION app, which was well perceived by users in a study conducted to check the feasibility of the system [Feedback helped users to perform the exercises correctly. The real-time qualitative and quantitative Feedback was displayed using a 2D animation and a numerical counter that depicts the joint angle. Moreover, a Color-Coded mechanism helped them to identify if they are within or outside the reach of the Target that helped them to perform the range of motion exercise as accurately as possible.feedback . They foe system . It was Feedback, Cavalcanti et al. were able to identify multiple aspects which might help to design future rehabilitation applications [Text Feedback was perceived better than Image Feedback. However, it was reported that it is critical that the display duration of the text is not too short to be able to understand the message clearly. For Image-based Feedback, the authors used a gif illustration that failed to convey the exact beginning and ending of a movement. Scores, on the other hand, helped to increase Adherence, i.e., to continue playing the game. Overall, Cavalcanti et al. reported that all forms of Feedback helped in some way to make correct movements and have the potential to motivate users in a physical rehabilitation setting.Investigating different forms and modalities of ications . For exaVisual Guidance elements. What worked well for one application might not work at all for another. Our main insights can be summarized as follows:Even for non-game-like applications, the use of AR/MR still provides a certain fascination and helps to keep users engaged. Still, if this is just a rather short-dated novelty effect or can be something that is sustained over time, remains to be seen.Visual Guidance elements and certain Medical Purposes, such as Gait & Balance being addressed through Obstacle elements. However, again, the current body of work does not provide systematic studies of such aspects but base this conclusion on the overall evaluation of an application.There is some evidence that there is a closer relation between specific types of There is growing evidence that simple video-based tele-rehabilitation approaches can not compete with AR/MR approaches, which should provide an interesting opportunity for future business models, as currently tele-rehabilitation and tele-fitness courses dominate the home market.Overall, the current state of research makes it difficult to draw generalizing conclusions. Many factors influence the choice and suitability of certain Output Technology is seemingly unrelated to the publication date, as seen in Screen remains the predominant choice of display across the entire period under review. In total, Screen-based approaches account for 56% of output devices, while Head-Mounted Displays (HMD) are only used in 26% of the applications. The immense technological advances over the last 10 years for HMDs and in particular AR/MR-HMDs, including lighter hardware, more user-friendly interfaces, and increased immersive potential due to greatly improved specs, have only very recently seemed to emerge in the field of physical rehabilitation. From 2019 on, the number of such applications has risen and reached some levels of consistency in the amount of use - surprisingly not to the detriment of Screen-based approaches, which remained the most-used technology even in 2019 and 2020.The choice of Output Technology can be found regarding the Affected Body Part as well as Bodily Function as shown in Screen-based approaches for upper body parts compared to Lower Body parts. In addition, we also could not find any influence of the potential Added Value on the choice of Output Technology.A certain level of influence on the Reasoning behind Technology Choices: To gain a better understanding of the reasoning behind technology choices for Output Technology, we conducted an additional in-depth qualitative analysis among the most recent references from our data-set, published in 2019 and after. The analysis showed that only a fraction of the considered references provides any justification for the selection of the Output Technology. These justifications then differ again between the type of visualization technology chosen, AR/MR or VR, and the type of hardware selected, e.g., HMD or Screen-based.The choice of VR: The use of VR, for example, is being discussed controversially. As a major disadvantage of VR, it is argued that patients do not receive feedback from the real world, which can lead to great insecurity and even health risks, especially for stroke patients who often suffer from balance problems [problems ,50,51. Iproblems ,53 or alproblems .The choice of AR/MR: There are also differing opinions on whether and where AR/MR is suitable for use, some of which may be caused by unclear definitions of AR and/or MR. For example, Theunissen et al. claim that a property of MR is the filtering out of real visual information, which can then lead to safety risks due to the shielding form the real world, similar to VR [ar to VR . Howeverar to VR . It is nThe choice of Screens: The main reasons given for selecting either Mobile Phones or other Screens were that these are inexpensive and commercially available. In addition, patients are usually familiar with their operation [Mobile Phones and other Screens are commonly found in households. One disadvantage of screens mentioned was the more difficult hand-eye coordination and split attention, since the visual attention cannot be on both, the own body and the screen simultaneously [peration ,50. Refeperation  and espeaneously .The choice of HMDs: HMDs primarily offer an advantage in representing the depth of motion in 3-dimensional space [HMDs is the impairment of head movement or an entire range of motion due to the inherent weight of the HMD and patients not being accustomed to carrying anything on their heads during movements or exercises [al space ,48. Theyal space . A majorxercises .Condition and age, e.g., limitations in Gait functionality, Balance, and prior experience using technology [A general implication to be taken from this analysis is that the choice of output technology depends on specific characteristics of the patient’s chnology ,51. Furtchnology , which mPhysical Rehabilitation, which we summarize below and which we think can help to guide future research:Neurological conditions, especially Stroke. This may be due to research grants rather being provided to researchers who try to tackle such universal problems. Still, it would help if more research would then try to generalize the findings to other Medical Conditions. In particular, research dealing with AR/MR-based interventions following Injury or physical Disabilities is severely lacking.The analyzed literature reveals a strong focus on rehabilitation following Upper Limb is both more prevalent in general and more diverse, routinely focusing on individual joints and muscles, which at least can be partly explained through the importance of the Hands (and related body parts) for everyday activities and independence. Contrary, a majority of Lower Limb research targets Gait or Balance. The research focused on the use of AR/MR technology in rehabilitation and exercises of individual joints and muscles of the Lower Limb remains scarce. Additionally, research aimed at muscle Strength is severely underrepresented as well, in particular for Lower Limb.Research on Output Technology, Screens still account for almost half of all display types used, even in most recent years. In contrast, there is ample research opportunity for more advanced AR/MR technologies such as HMDs and Spatial-AR through projection. HMDs might have an advantage for home-based exercise, but Spatial-AR could be installed in facilities and provide much of the same experience without the drawbacks of a (currently) heavy-weight head-worn device.Regarding the utilized Visual Guidance elements Virtual Coach and on-body Overlays are relatively seldom types of demonstration, although the existing research shows promising results . Whi. WhiVisuVisual Guidance elements. While a few references did compare elements [Furthermore, there is a lack of research explicitly comparing the effectiveness and advantages of selected elements ,28,30, tBased on our analysis, we identified a number of trends and open issues in AR/MR research within the field of There are some limitations and potential weaknesses of this literature review that could be addressed in future research.Firstly, in this scoping literature review, information was gathered from different studies and sources without assessing or weighing the quality, accuracy, and validity of the papers. Instead, the focus was on collecting evidence to provide an overview of the research topic and assist researchers. Therefore, no assertions or suggestions can be made about the feasibility of the employed visualisations, nor is possible to derive a fair general comparison between them.Furthermore, the review was exploratory, employing an open-coding process. Therefore, the chosen categories, codes, and assignments could be considered arbitrary. In order to mitigate this factor, all steps leading to and including the final coding process were performed by at least two independent researchers and discussed with a third reviewer before a final call was made.The selection of search keywords is, as with every literature review, a topic for debate. We deliberately did not impose a predefined set of keywords on the search process, but rather applied an iterative process, adding relevant keywords along the way.Lastly, within this review, we identified distinct applications. Occasionally, this led to an inclusion of several such applications presented within a single reference or by the same research group. Although distinct, these routinely share many similarities, such as using the same technology, thereby distorting results. Therefore, the results do not accurately describe the amount and quality of research in each category. In order to limit this bias, we did not include papers describing an identical system, but only the one best representing it.Besides the above-mentioned limitations, our approach offers a number of strengths summarized in this section.The review address the broad topic of the use of Augmented and Mixed Reality applications in several areas of medical rehabilitation and for multiple conditions and affected body parts. Further, it takes into consideration a broad spectrum of sources, employing different methods and study designs. It is therefore able to provide an overview of the extent, range and nature of currently evolving areas of research as well as summarize research findings.By doing this, it also aids to identify trends, needs and research gaps to aid in future research.The review further provides a first taxonomy to classify the research area. The advantage of the exploratory approach employing an open-coding method lies in its bottom-up construction of categories and items based on actual research and relevant items within the sources.Additionally, several in-depth qualitative comparisons of selected recent studies were conducted, to provide a better understanding of the reasoning behind technology choices for Output Technology, this paper aims to further guide future research and experiment set-ups.Patient Types, the Medical Purpose as well as the Interaction Design of proposed applications. In particular, the latter explores the relationship between Output Technologies, Application Types, Input Technologies and Visual Guidance elements. We identified 13 distinct, reoccurring abstract types of elements providing Visual Guidance, which we classified further into the three subgroups Guided Interaction, Demonstrated Interaction and Feedback. A deeper analysis of the selected data-set revealed the positive relationship between elements and the Medical Purpose as well as some insights into the effectiveness of certain Visual Guidance elements. We also presented qualitative evidence for researchers’ reasons for selecting certain Output Technologies. In summary, the taxonomy provides an overview of relevant attributes of AR/MR applications for physical rehabilitation. It bridges the gap between a medical/physiological perspective  and the Technology and Interaction Design. We are confident that it can serve as a reference for new research and practitioners alike, who aim to develop new approaches or get an understanding of existing work in a specific subarea. In particular, the set of Visual Guidance elements can serve as an inspiration for future Interaction Designs. The taxonomy also revealed the predominant motivation to develop technological solutions for physical rehabilitation process; the two biggest problems, based on what has been addressed in research, seem to be the lack of autonomy (or reliance on the presence of a therapists) as well as the lack of motivation (which often might be co-related with the absence of a therapist). Most researchers do not want to replace the therapist but either see the need for additional physical exercise or think that additional technology would help therapists to focus more on individual patients. The lack of motivation is mainly tackled by Game-like Application designs or gamification elements, such as Performance Feedback. Although our focus was on AR/MR applications, which are nowadays often naturally associated with HMDs, such as a Microsoft HoloLens device, most applications still use screens in a variety of form factors to provide visual guidance. Even though some researchers acknowledge the difficulties of split-attention and the less immersive experience of such Screen-based approaches, the wide availability, low cost, and technical limitations of HMD-based approaches  may help to explain this situation.We analyzed 114 applications presented in 91 papers within the field of AR/MR research regarding physical exercises in medical rehabilitation. Employing an open coding process, we derived a taxonomy that distinguishes between different Screen-based approaches; (2) atudies comparing and understanding the efficacy of different forms of Visual Guidance and Application Types; (3) the tackling of currently underrepresented Body Parts or Bodily Functions.Given that, we pointed out a variety of research opportunities. In particular, we want to highlight the following three areas we see as critical for future research: (1) applying and studying the efficacy of advanced AR/MR technologies to overcome the limitations of Finally, we want to stress the importance of multidisciplinary research in this area. Only a combination of experts from the medical field as well as HCI  is able to address the taxonomy as a whole and make sensible technology and medical application choices.


For the purpose of comparative research, MSWIBA before valorization, after valorization, and after NaOH pre-treatment was investigated. In terms of their physico-chemical properties, the tested samples were examined. Three kinds of MSWIBA were used as a substitute for 30% of cement in mortars. The mortars were tested for 28-day strength. Leachability tests were performed in acid, aggressive, alkali, and neutral water environments. Life Cycle Assessment (LCA) analysis was carried out, which presented the environmental benefits of MSWIBA management in construction.This study aims to investigate the possibilities of municipal waste incineration bottom ash (MSWIBA) utilization in the construction sector. MSWIBA development fits into the European Green Deal, Sustainable Development Goals (SDGs), and the Circular Economy (CE). This manuscript describes current MSWIBA treatment such as solidification, ceramization, vitrification, chemical activation (NaOH, CaOH In the United Nations Framework Convention of 1992, a position was adopted stating the danger of raising the average global temperature by 2 °C (or even 1.5 °C) above pre-industrial levels . Figure To improve the condition of the environment, the European Union introduced the European Green Deal . The oveThe green deal is integrated within the sustainable development goals (SDGs) adopted by the United Nations. The management of secondary waste in construction is in line with SDG 12 (Ensure sustainable consumption and production patterns) and SDG 13 (Take urgent action to combat climate change and its impacts), and can extend the life cycle of products or materials ,10.2) and reduced extraction of natural resources. Emissions related to the extraction, processing, and use of energy are avoided. To produce a ton of cement, almost one ton of CO2 (dependent on technology) is produced [The use of secondary waste as a building material can contribute to achieving climate neutrality and lower pollution in Europe . Using wproduced .The present research aims to analyze the possibility of recycling secondary waste from incineration plants. This is in line with the New Circular Economy Action Plan of closing the loop, which The last element of a circular economy is energy recovery. Combustion of mixed (non-recyclable) municipal solid waste (MSW) is part of Clean, Reliable, and Affordable Energy. MSW that cannot be recycled is landfilled, but this is not part of the circular economy ,14.An exemplary installation with a capacity of 210,000 tons per year and an average calorific value of incinerated waste at the level of 7.8 GJ/Mg (GJ/ton) produces 300.370 GJ of thermal energy and 405.166 GJ of electricity annually ,15.The combustion of MSW in incineration plants generates more than 30% of secondary waste concerning the inlet stream. The main residue is MSW incineration bottom ash (MSWIBA), which accounts for ca. 90% of MSW incineration solid residues. About 18 million tons are produced annually in Europe even with efforts to reduce waste incineration; hence. the amount of MSWIBA is much greater worldwide, such as in China, Japan, and Singapore . MSWIBA MSWIBA is characterized by compatibility with high elasticity in its uncured state. In the construction industry, MSWIBA, thanks to its properties, can replace natural aggregate and be used as a construction material. However, to be used in the construction industry, MSWIBA should be subjected to valorization and appropriate processes. Fresh MSWIBA is metastable and strongly alkaline reactive . One of the methods of safe MSWIBA management, compliant with the Reference Document on the Best Available Techniques for Waste Incineration, is its valorization, generally achieved by the steps described in the following manuscript .2, NA2SiO3 + NaOH, Na2CO3 + NaOH, NH4OH), acid treatment with dilute solutions , chemical stabilization , chelation, and other technologies depending on the needs, which are determined by the physicochemical composition and intended use of the end product. Ceramization and vitrification are high temperature processes and therefore are expensive, energy intensive, and non-environmentally friendly. Stabilization, solidification, and storage do not provide for recovery, and hence, do not fit into the circular economy. Other processes are still new, little known, and relatively expensive. This is why a market gap still exists; pilot and laboratory research is needed to fill this gap [To improve the quality of MSWIBA as a substitute for natural aggregate, sand, or cement, the concrete matrix can be compacted or different activation can be used, for example: solidification, ceramization, keramization, vitrification, chemical activation  is partly used as a priming method in the building industry . CurrentEven after the described valorization process, the MSWIBA still contains mobile pollutants, e.g., heavy metals and salts, which are harmful to the environment. In addition, it contains substances that may have a negative effect on the concrete mix, such as metallic aluminum, glass, sulfur, chloride, and gypsum. Thus, using “raw” MSWIBA as a substitute for natural aggregate would produce a material with worse physical and chemical properties than the conventional one. Cracks and swelling are often noticed in concrete samples with the addition of MSWIBA due to its metallic Al or Al/Zn alloy content .One possibility to reduce these adverse effects is to pre-treat the raw MSWIBA with NaOH. Equations (1) and (2) present the reactions of undesired Al and Zn, for instances, with NaOH:NaOH pre-treatment reduces the leachability of MSWIBA impurities  and improves building properties. An important parameter for this pre-treatment is the concentration of NaOH. The use of a solution below 0.1 mol/L NaOH may not be effective. Due to the seasonality and heterogeneity of MSWIBA, to select the optimal concentration of the NaOH solution, a specific batch of material should be previously tested, mainly for its content of Al and Zn, to provide for the proper amount of NaOH as indicated by the stoichiometry in the given reactions (1) and (2) .The course and effectiveness of the NaOH pre-treatment process depends not only on the concentration of NaOH, but also on the temperature and duration of the process ,19.To improve the pre-treatment, the stabilization time can be extended. However, some researchers have shown that the compressive strength can be increased with the appropriate ratio of aggregate to MSWIBA and if water pre-treatment is used .In previous work, researchers investigated how different mass ratios of MSWIBA to aggregate values influence the compressive strength of cement . The besIn the present work, the aim is to check how leachability in different environments  changes for mortars prepared with different types of MSWIBA. In particular, the mortars were prepared with addition of MSWIBA before valorization, after valorization, and after NaOH pre-treatment.Every time a new process is proposed for recycling or recovery a waste stream, it is almost compulsory to check whether the new process effectively offers environmental improvements compared to conventional processes by performing a Life Cycle Assessment (LCA) .Several authors have attempted to carry out an LCA of various MSWIBA management methods and the results indicate that the use of slag after waste incineration is associated with a positive environmental impact ,24,25.Results from one author noted up to 19% cost savings from waste-derived alkali-activated mortar in comparison to conventional alkali-activated mortar. Authors predict that chemically modified waste-derived activators are a promising alternative for improving the environmental performance of alkali-activated materials if their usage also reduces or replaces the need for conventional alkali-activators .This study aims to provide a preliminary evaluation of the environmental impacts or benefits of using NaOH treatment for the alkali activation of MSWIBA by LCA.MSWIBA were sampled from a MSW incineration plant before a and aftThe samples of MSWIBA before and after the valorization and after the alkali activation were tested to check their construction properties and environmental behavior, and was leaching compared to environmental standards. In addition, phytotoxicity tests were carried out.For each sample, the following characterizations were performed. Moisture was determined in accordance with PN-Z-15008-02: 1993; total carbon (TC) in accordance with PN-EN 15407: 2011; total sulfur (S) in accordance with PN-ISO 351: 1999; chlorine (Cl) in accordance with PN-ISO 587: 2000; heavy metals in accordance with PN-EN 16174: 2012, PN-EN ISO 11885: 2009. The water extract was prepared in accordance with the PN-EN 12457-2: 2006 standard, and selected components were measured in accordance with the PN-ISO 9964-2/Ak: 1997 standard. Building mortars were produced. Thirty percent of the MSWIBA was used for each of the mortars as a substitute for CEM I 42.5R cement. Mortar composition was: 135 g of MSWIBA, 315 g CEM I 42.5R, 225 g of water, and 1350 g of sand, according to the PN-196 standard. The mortars were made in accordance with the PN-EN 480-1 standard ,27. Mort2CO3 (slightly acidic pH), and the neutral environment was prepared with distilled water . For comparison purposes, the samples were shaken in the same condition, at room temperature, and for the same time (24 h).To test the leachability, an extract from the blocks was prepared in accordance with the PN-EN 12457-4: 2006 standard . Mortar For the environmental comparison of the different valorization possibilities, a Life Cycle Assessment (LCA) was applied. The impact assessment method used was ReCiPe 2008, calculated with the aid of SimaPro 8.0.○Eighteen detailed waypoints that are relatively accurate but difficult to interpret;○for human health;about the ecosystem;for natural resources.Three simple to understand, but more imprecise endpoints:There are many methodologies for LCA. One of them is ReCiPe, which is a methodology to bring together the endpoint and midpoint of environmental analysis . The most important goal of ReCiPe is to transform a long list of LCI (life cycle inventory) results into a limited number of indicators. These indicators express the relative environmental impact. The ReCiPe methodology defines two levels of indicators and each user can choose on which level they want the score:The user can choose between indicators and correctly interpret the indicators as part of a specific analysis. Another advantage of the methodology is the possibility of weighing the final results and presenting simplified values for the entire analysis . We express the values in DALY units for human health, species.yr for ecosystems, $ for resources.Human health, expressed as the number of years life lost and the number of years lived disabled. These are combined as Disability Adjusted Life Years (DALYs), an index that is also used by the World Bank and WHO. The unit is years;Ecosystems, expressed as the loss of species over a certain area, during a certain time. The unit is years;Resources surplus costs, expressed as the surplus costs of future resource production over an infinitive timeframe , considering a 3% discount rate. The unit is 2000US $.The endpoint characterization factors used in ReCiPe can be described as follows:Individual weights for given categories are implemented in the software, which is a tool for analysis, e.g., SimaPro, on which this study is based. They can also be changed if there is a need to modify the significance of individual components of the environmental impact categories. Program indicators were used in the presented analysis.The goal was to analyze the environmental impact of three similar concrete blocks produced using three different scenarios of MSWIBA treatment. Scenario 1 includes the analysis of a standard concrete mix block, Scenario 2 includes the analysis of a concrete mix block with MSWIBA without NaOH treatment, and Scenario 3 includes the analysis of a concrete mix block with slag and NaOH treatment. The assumptions of the three scenarios are presented in 2O, 1350 g sand, and 157.5 g NaOH (50%) for the MSWIBAAV pre-treatment process before making the mixture, after valorization.The study aim was to compare the environmental performances of the following production processes of one concrete block weighing 2.025 kg : (i) standard concrete mix, without the use of slag, with CEM I 42.5R cement; (ii) production of a block using MSWIBA slag after valorization as a replacement for 30% CEM I 42.5R; (iii) production of concrete mix by the assumptions made for one concrete block, which is the basis of the article. For production, we used 135 g MSWIBAAV, 315 g CEM I 42.5R, 225 g HThe system boundaries include the process using basic materials in concrete production and using the BAAV as a part of raw material in scenarios 2 and 3. While they do not include the processes related to the slag valorization, they are the same in the three cases. The analysis does not include the energy consumption and consumption of other substances, or the waste flows or transportation during the production, because these are the same in the 3 scenarios. The analysis of Scenario 3 includes additional NaOH consumption, which is needed for the pre-treatment process. The analysis does not include the heat needed for the pre-treatment process because the assumption is that waste heat can be used from the factory where MSWIBA is produced, valorized, and pretreated. Primary data were used for the mixture composition. Secondary data were provided using the appropriate records of the Ecoinvent database.MSWIBA before valorization contains pollutants such as glass (18%), porcelain (0.5%), and metals (0.1%). MSWIBAAV is metal-free because of the valorization process, in which ferrous and non-ferrous metals are separated.NaOH pretreatment was performed to etch the contact surface of MSWIBA. Alkali soaking increases the contact surface with the binder.All three bottom ash samples were light grey and non-dusting, without a characteristic smell.Carbon does not change in all samples;Sulphur decreases from 0.48% in MSWIBA before valorization to 0.20% in MSWIBA after valorization and 0.07% after NaOH pre-treatment;Chloride decreases from 0.41% in MSWIBA before valorization to 0.12% in MSWIBA after valorization and <0.01% after NaOH pre-treatment;Manganese decreases strongly after valorization (from 1178.35 ppm to 463.46 ppm) and less strongly after NaOH treatment (403.04 ppm);Nickel decreases after valorization, but does not decrease after NaOH treatment;Lead decreases after valorization, but less strongly after NaOH treatment;Cobalt decreases after valorization and after NaOH treatment;Chrome decreases after valorization and after NaOH treatment;Copper decreases after valorization and decreases more after NaOH treatment.MSWIBA before valorization, MSWIBA after valorization, and after NaOH research present that:The contents of the undesired compounds such as sulfur, chloride, and most heavy metals strongly decrease from samples before valorization to samples after NaOH pre-treatment.In the case of samples after the valorization process, the removed content of the different substances is expected to be found in the other solid streams mechanically separated from the main one , and likely in the recovered metal streams.The further decrease observed for samples after the NaOH pre-treatment needs a more accurate study. The amount of each compound removed will be found in the exiting NaOH-rich liquid stream. Thus, a full characterization of this stream is needed in future experiments to perform a complete mass balance for each substance and to understand which kind of treatment can be applied at an industrial scale to comply with environmental regulations.The mortars with MSWIBA after NaOH pre-treatment present slightly higher values of bending (+15%) and compressive (+1%) strength than mortars with MSWIBA after valorization.The research indicates the necessity to carry out the slag valorization process. The lack of the valorization process causes the mixture to swell. The mixture swelling excludes MSWIBA from being implemented in the industry. Research shows that NaOH pre-treatment has a positive effect on the strength of the mixture. The NaOH treatment process may vary. The final effect of MSWIBA on the physicochemical properties is influenced by the concentration of NaOH, the NaOH ratio, the processing time, and the temperature of the process.The results show that the leaching of pollutants depends mainly on the water environment’s pH. The lowest leachability was noticed in the case of a neutral environment in which distilled water was used. The greatest leachability was in aggressive and alkaline water environments. The leachability is also influenced by the alkali pre-treatment, where in the case of Ba, the leachability is lower for blocks with MSWIBA after NaOH pre-treatment, while it is rather constant for Li. Na leachability increase was noted for mortars with MSWIBA after NaOH pre-treatment, as is evident because the concentrated NaOH solution was used.Unfortunately, in the environment, ideal laboratory conditions do not exist, but in Europe, the majority of soil is acidic. This translates into less leaching of contaminants when using bottom ash as a building material in comparison with an alkaline environment .The results of the research indicate the need to study the leachability of pollutants through sequential extraction due to different bioavailability. Sequential extraction distinguishes between water-soluble, ion-exchange, hydroxide, organic-related, and residual fractions. In the case of the techniques usually used in research, i.e., with distilled water, the leachability is the lowest. The low extraction effect is due to the lack of buffering capacity and high solubility of organic compounds. The ion exchange fraction uses the adsorption and desorption process. The hydroxide fraction takes advantage of the reducing properties of the compounds. The carbonate fraction leaches under conditions of lowered pH, e.g., acid rain and oxygen deficiency .The analysis of the three scenarios was made based on assumptions using SimaPro software ReCiPe EndPoint V1.12/Europe ReCiPe H/A method in three general impact categories: human health, ecosystems, and resources.The benefits associated with the use of MSWIBA are included in the data used from the Ecoinvent database. The results of the LCA analysis were compared in In all impact categories, the results for the concrete block without the use of slag are the highest. The results showed that the environmental burden of using NaOH is higher compared to the slag-based block without NaOH pre-treatment, because the addition of NaOH is harmful to the environment compared to the valorization process itself. It is obvious, but the load values for most of the impact categories for scenarios 2 (s2) and 3 (s3) are the maximum difference in the human health category: s2 ~50% less DALY and s3 ~30% less DALY. s2 around is 45% less $ in the resources category, while the impacts of s1 and s3 are similar (around 1.5% lower impact for NaOH treatment). In the ecosystem category, the impact is 35% for s3 in comparison to s1, and is more than 50% lower for s2.The LCA in this case is only an estimation to provide first view of the environmental aspects. In comparison to different LCA for using slag or fly ash in concrete production, we can observe that the environmental impact in most of the categories is more environmentally friendly than conventional production .Future study including more specific data is required to check all parameters and variables. However, the first positive results come from this study. In the sensitivity analysis, the main contributor in the presented case with NaOH treatment is NaOH. If we change the production process of NaOH, the results are similar. In the LCA, the average production process of NaOH was used, but between NaOH production process, the difference is the highest for the human health category, around 7% in Process 2 compared to the other processes (1 and 3).Samples of MSWIBA before and after valorization and after NaOH pre-treatment were characterized. It a decrease in heavy metal contents after valorization and a further decrease after NaOH pre-treatment were noted.The addition of 30% MSWIBA after NaOH pre-treatment to concrete mix slightly improves the bending and compressive strength of the concrete obtained.Leaching test results of concrete mixes obtained by adding 30% of MSWIBA before or after valorization or after NaOH pre-treatment show that, in general, the NaOH pre-treatment allows for pollutant reduction.Therefore, this article proposes an initial LCA analysis for the analyzed scenarios with or without the use of NaOH for pre-treatment in order to examine the environmental impact of the proposed slag valorization method in comparison to standard concrete block production. The benefits of the slag process with NaOH pre-treatment are not only linked with production, but are also relevant later during the use phase, because the leachability of the heavy metals can be reduced.Despite the use of NaOH, concrete mix created without slag has an almost twice as great environmental burden as the other two methods: with the use of slag with and without NaOH treatment. It should also be emphasized that this preliminary analysis does not take into account the positive benefits related to the lack of leachability of heavy metals into the environment and the increased strength of the concrete blocks, which far outweigh the negative effects of using NaOH in the pre-treatment process ,31.The slight negative environmental impact of using NaOH can be reduced by reusing it after the process and/or reusing it in another technological process, or by reducing the concentration from the 50% concentration used in this analysis. It seems obvious that post-process NaOH is a product that can be reused; hence, its environmental impact on the process itself after pre-treatment will be beneficial. According to the environmental analysis, the use of slag in the production of concrete mix gives a positive result and additionally, thanks to NaOH, we can reduce the leaching of heavy metals during the use of the material in construction and increase the strength and durability of the concrete, which presents another positive impact on the environment.The conducted research has an impact on increasing social awareness in the field of waste management and climate change. Secondary waste recycling reduces negative anthropogenic impacts on the environment. The basic research conducted has implementation potential. Implementation can take place in an incineration plant or a separate installation, e.g., an installation for the production of concrete. MSWIBA can be used for the production of paving stones or industry halls.The NaOH pre-treatment research is relatively new in the market. Examples and detailed NaOH pre-treatment are described in reference . AlkalinThe different presented natures of the water environment were intended to imitate real conditions. The test with distilled water is the reference test. There are different types of soil in the world. Soils are distinguished on the basis of pH: strongly acidic (pH < 4.5), acidic (pH 4.5 > 5.5), slightly acidic (pH 5.6–6.5), neutral (pH 6.6–7.2), and alkaline (pH > 7.2). If concrete is placed in soil, the soil’s pH will have an effect on the leachability of contaminants. The research shows the most favorable pH for the leaching of pollutants from the product.2O2 and moderate NaOH could improve the processes [E. coli bacteria [Despite the fact that NaOH in high density seems to have high impact on the environment, the benefit of using it is less leaching from the concrete block. Additionally, the NaOH can be reused in different processes of waste management, for example, to increase biogas production , to elimrocesses . The NaObacteria . This re