The ideal engineered vascular graft would utilize human-derived materials to minimize foreign body response and tissue rejection. Current biological engineered blood vessels (BEBVs) inherently lack the structure required for implantation. We hypothesized that an ECM material would provide the structure needed. Skin dermis ECM is commonly used in reconstructive surgeries, is commercially available and FDA-approved. We evaluated the commercially-available decellularized skin dermis ECM Alloderm for efficacy in providing structure to BEBVs. Alloderm was incorporated into our lab’s unique protocol for generating BEBVs, using fibroblasts to establish the adventitia. To assess structure, tissue mechanics were analyzed. Standard BEBVs without Alloderm exhibited a tensile strength of 67.9 ± 9.78 kPa, whereas Alloderm integrated BEBVs showed a significant increase in strength to 1500 ± 334 kPa. In comparison, native vessel strength is 1430 ± 604 kPa. Burst pressure reached 51.3 ± 2.19 mmHg. Total collagen and fiber maturity were significantly increased due to the presence of the Alloderm material. Vessels cultured for 4 weeks maintained mechanical and structural integrity. Low probability of thrombogenicity was confirmed with a negative platelet adhesion test. Vessels were able to be endothelialized. These results demonstrate the success of Alloderm to provide structure to BEBVs in an effective way. However, polymers can lead to graft failure due to the body’s natural foreign body response leading to a persistent inflammatory response7. The hydrogel grafts are completely biological and thus illicit minimal immune response, however presently the most effective current way to achieve sufficient strength is to subject these vessels to mechanical conditioning for several weeks to months, which has impeded manufacturability and translatability. Another common approach to engineer blood vessels is to roll cell sheets into tubes creating a completely biological construct8. However, this approach still requires weeks of strength conditioning. A more efficient approach for introducing the strength is needed for implantation.Current technologies in vascular tissue engineering rely on polymer tubes as a scaffolding material or cell sheets wrapped into a tube. Leading approaches share the same basic principles- seeding of vascular smooth muscle cells onto a tubular scaffold such as a polymer11. The extracellular matrix of the adventitia allows for a vessel to withstand high pressures preventing vessel rupture12. The strength derives from the significant type I collagen content, which is a load bearing extracellular matrix protein that is able to resist high pressure forces16. The adventitia also contains elastin to aid in elasticity and vessel distension17. Collagen is found in many organs, with especially high levels in the skin. Specifically, the ECM of the skin dermis consists of type I collagen and elastin to aid in strength and elasticity18, thus providing an ECM similar to that of the adventitia. Decellularized dermis ECM has been used for years in reconstructive surgeries and for wound care, with several products currently on the market19. One product in particular, Alloderm, has been used extensively in the clinic with much success. Alloderm is a human allograft, and has been used for reconstructive surgeries, complex abdominal wall hernia repair, soft-tissue defect augmentation, rhinoplasty, and vaginal repair22. Alloderm has also been investigated for other uses such as for tendon repair, stress urinary incontinence and pelvic organ prolapse repair24. The mechanical properties of the ECM of Alloderm, and the fact that it is decellularized thus reducing inflammatory and rejection risk, makes it ideal for tissue engineering application27. Thus, we proposed to employ the advantageous properties of Alloderm to mimic the adventitia’s role and provide strength to engineered blood vessels. This type of application of a decellularized matrix is a departure from the typical use of decellularized matrices as a scaffold for use in its tissue of origin. Our approach represents an innovative application of a decellularized ECM for use as a reinforcement material in an engineered tissue of a different tissue origin. Our objective was to mimic the natural strength component of a native blood vessel by substituting a comparable ECM.We hypothesized that using a human-derived, biological material for mechanical strength as opposed to polymers commonly used in the field will provide an effective support structure that will meet the mechanical needs of a vascular graft and minimize adverse immune response. In a native blood vessel, the adventitia outer layer is key to providing structural integrity30, Alloderm was integrated into our protocol. In our methods, vascular cells are formed into ring structures, which are then stacked into tubular form to form the vessel. This method is termed the Ring Stacking Method (RSM). This method is highly modifiable and allows for the integration of reinforcing materials such as Alloderm. Once the Alloderm material was successfully added to our RSM protocol, the resultant engineered rings and vessel structures were tested mechanically. Tensile tests revealed that the Alloderm-integrated engineered vessels reached a tensile strength of 1500 ± 334 kPa, which is in the range of a native vessel’s tensile strength of 1430 ± 604 kPa12. Burst pressure reached 80 mmHg, indicating that the decellularized ECM was able to increase the completely biological engineered vessels blood pressure capabilities to within the diastolic blood pressure range. Histological analysis showed that the overall collagen amount and degree of fiber maturity were significantly increased, elements that both contribute to tissue strength. These results demonstrate the success of Alloderm to provide sufficient mechanical support to the BEBVs in a much more efficient and effective way than current approaches in the field. The novelty of this approach is in achievement of clinical requirements for engineered vessel mechanical strength using decellularized ECM, progressing this type of technology that much closer to patient use.Using our lab’s unique method for generating completely biological engineered blood vessels (BEBVs) as our base structureHuman dermal fibroblasts (HuDFs)  were used to make adventitia-based engineered vessels. Dermal fibroblasts were chosen in foresight of patient application of autologous cells. Passages up to 15 were able to form consistent rings/vessels. Fibroblast growth media (GM) consisting of 89% Dulbecco’s Modified Eagle Medium (DMEM), 10% fetal bovine serum, and 1% antibiotic/antimycotic was used to expand and maintain the cell culture. Cells were trypsinized at roughly 90% confluency and used to make the rings and vessel structures.l-Glutamine (200 mM); 1% antibiotic/antimycotic; 50 µg/mL ascorbic acid; 1 µg/mL hydrocortisone; 4 µg/mL heparin sulfate; 15 ng/mL insulin-like growth factor-1 (IGF-1); and 5 ng/mL of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor-basic (FGF-b).Human umbilical vein endothelial cells (HUVECs)  were used to form the intima in the Alloderm vessels. HUVECs were cultured in HUVEC growth media consisting of 93%—131 media; 5% FBS and Human saphenous veins were obtained from diabetic patients undergoing limb amputation between years 2018–2020. The study was approved by the Human Institutional Review Boards of both entities of Wayne State University and Henry Ford Health System . Informed consent was obtained from all 6 patients who donated tissues. The tissues were obtained in accordance with relevant guidelines and regulations.Fully intact human femoral arteries were harvested from fresh, non-treated cadavers donated to the Wayne State University Body Bequest Program. Arteries were tensile tested to determine mechanical properties and histologically processed to assess tissue morphology.A 60 mm petri dish was used as the basis for forming the rings. Poly(dimethylsiloxane) (PDMS) polymer  was used to coat plates at 3 mL per plate. Posts were made and adhered to the plates centrally to provide a structure around which the rings would form. The posts were punched from PDMS bulk material using 6 mm diameter biopsy punches to fabricate 6 mm lumen vessels. Base plates were coated with PDMS, followed by placement of the post centrally in the plate and oven cured at 60 °C for 1 h. Plates were sterilized with a 30 min 70% ethanol soak followed by 30 min of UV sterilization under the bio-hood.28. A 4:1 ratio of 20 mg/mL bovine fibrinogen  to 100 U/mL bovine plasma thrombin  was prepared. Hydrogel media consisted of 88.8% DMEM, 0.1% TGF-β and ascorbic acid, 10% fetal bovine serum, and 1% antibiotic/antimycotic.A provisional hydrogel was used to secure the cell sheet as it aggregated around the central post to form the ring structures. Hydrogels rapidly degrade in 2–4 weeks hence serving as a temporary support. Fibrin gel was identified as an ideal option as it is naturally found in the body. Fibrin hydrogels were formed using thrombin, fibrinogen, and hydrogel mediaAlloderm was obtained from LifeCell Corporation . Biopsy punches were used to cut 6 mm holes into Alloderm. A scalpel was used to cut a 3–3.5 mm width around the 6 mm hole. The final dimensions of the donut shaped Alloderm was an inner diameter of 6 mm and outer diameter around 12–13 mm. Alloderm donuts were sterilized in a bio-hood using UV sterilization for 15 min on both sides and kept sterile until ready to use.6 fibroblast cells in 4 mL GM, 150 µg ascorbic acid and 0.01 ng TGF-β either onto fibrin gel directly (basic rings/vessels) or fibrin gel topped with Alloderm (ECM-integrated rings/vessels). Media was changed one day after seeding, and subsequently every 3 days for 14 days. Each media change was supplemented with fresh ascorbic acid and TGF-β.Cultured fibroblasts were trypsinized from pates and re-suspended in growth media. Each prepared PDMS ring plate was seeded with 1.5 × 10To create the vascular grafts, tubular structures were created by stacking 3 or more engineered rings. Alloderm adventitia vessels were created using our lab’s Ring Stacking Method (RSM). In the RSM, engineered vascular rings are stacked around a 1.2 cm long 3D printed post placed centrally in custom made 8 cm tall plates. Engineered vessels made of stacks of 3 rings were used for histology and stacks of 6 rings were used for mechanical testing. Rings were temporarily adhered to one another using additional fibrin glue to secure the rings to each other as the cells deposited their own extracellular matrix to secure the overall vascular structure. A 1:1 volumetric ratio of 30 µL of 100 u/mL thrombin to 30 µL of 20 mg/mL fibrinogen was used for the fibrin glue. Ring stacks, i.e. vessels, were maintained in HuDF growth media supplemented with ascorbic acid and TGF-β for one week with a media change 3 days after stacking.To demonstrate the ability to scale the ring stacking method towards engineering vessels of physiologically relevant sizes, a 5 cm long adventitia vessel was created. Custom ring and vessel culture dishes were developed to accommodate the increased dimensions. The custom vessel culture dish consisted of a 50 mL conical equipped with a 5 mm diameter 3D printed polylactic acid (PLA) post holder attached to the center of the lid by PDMS. A 10 cm long, 5 mm diameter PLA post was printed, filed for smoothness, and thinly coated with PDMS to reduce ring attachment and deformation during stacking and vessel removal. A 60 mm culture plate with a central PLA post holder was utilized for stacking rings to maintain sterility of the vessel culture dish during the stacking process. All components were sterilized with 70% ethanol followed by UV radiation prior to cell culture use. Rings were formed per the Ring Formation protocol using human dermal fibroblasts. Following six days of self-organization, adventitia rings were gently removed from the wells with fine-tip forceps and transferred to the 10 cm PLA post fitted in the 60 mm stacking dish post holder. After the rings were stacked and fit closely together, 80 µL of thrombin (100 U/mL) and 80 µL of fibrinogen (20 mg/mL) were applied to the outer surface of the vessel to aid in ring-to-ring adhesion. Following ring stacking, the vessel post was transferred from the stacking dish and placed in the custom 50 mL conical post holder for culture. Forty-seven rings were used to build the 5 cm long vessel.6 cells/mL in HUVEC media were used to create a cell suspension. Luminal seeding was achieved by pipetting 600 µL of the endothelial cell suspension into the adventitia vessel lumen followed by sealing the PDMS shell with the second tube fitting. The cylindrical culture chamber was placed horizontally in a culture dish and incubated for 1 h. Following this period, the media with HUVECs was carefully removed by pipetting, the vessel was rotated 120°, and the endothelial seeding process was repeated until a full 360° rotation was achieved. Endothelial cell-seeded vessels were removed from the PDMS shell, placed into a traditional culture dish, and incubated in 50% HUVEC media and 50% fibroblast growth media for 24 h prior to analysis. The HUVEC-seeded Alloderm vessels were fixed in formalin for 24 h, dehydrated, embedded in paraffin, and sectioned. The vessels were stained with FITC-conjugated Ulex Europaeus (Gorse) Agglutinin I (UEA I) to mark the endothelial cell glycoproteins and glycolipids, and DAPI to mark nuclei.In preparation of endothelial cell seeding, adventitia vessels were transferred into an 8 mm diameter PDMS cylindrical shell with two removable 3D printed PLA tube fittings. Adventitia vessels were transferred from culture posts into the cylindrical shell with one fitting blocking the outlet. Human umbilical endothelial cells (HUVECs) at a concentration of 4 × 10To test long-term mechanics of the Alloderm-integrated engineered vascular tissue, rings with Alloderm (n = 10) were cultured for 4 weeks then tensile tested. Controls consisted of Alloderm rings tested immediately after formation, denoted as timepoint day 0. Rings were maintained in culture in fibroblast growth media supplemented with ascorbic acid and TGF-β. Media was changed every 3 days. Tensile testing was performed on a Mark-10 ESM 301  with a 1000 N load cell at a strain rate of 0.4 mm/min until failure. Samples were formalin fixed for 24 h, dehydrated, paraffin embedded and sectioned for histological analysis.Tensile testing was performed using an UStretch system with a 5 N load cell  and an Instron 5943 with a 50 N and a 500 N load cell . The smaller load UStretch was used for tensile testing in the range of the original rings and vessels without Alloderm. The higher load Instron was used to tensile test the Alloderm by itself, and Alloderm-integrated rings and vessels. Rings were tensile tested 14 days after cell seeding. Two modes of tensile testing were conducted to analyze both circumferential and longitudinal vessel mechanics. Circumferential tensile testing was used to measure the hoop strength of the rings and vessels. Longitudinal testing was used to measure the strength along the length of the vessels. Samples were stretched to failure and mechanical properties of elastic modulus, ultimate tensile strength and failure strength were obtained from resultant stress–strain curves.Circumferential tensile testing was conducted at a strain rate of 0.4 mm/min until failure. Rings with Alloderm (n = 5) and without dermis (n = 5) were tested to determine the effect of the addition of Alloderm. Alloderm donuts alone (n = 6) were tensile tested to determine their independent mechanical properties. For tensile testing, engineered vessels were built with 6 rings each. Vessels with (n = 5) and without (n = 5) Alloderm were tensile tested after a 7-day culture period following ring stacking. For control data, a human saphenous vein (cut into n = 6) obtained from a diabetic patient following amputation and a human femoral artery (cut into n = 8) obtained from un-embalmed cadaver were tensile tested.Longitudinal tensile testing was performed at a strain rate of 0.4 mm/min until failure. Engineered vessels with (n = 5) and without Alloderm (n = 5) were tensile tested following a 7 day culture period after ring stacking. In order to attach the vessels longitudinally into the tensile tester, VetBond tissue adhesive  was used to fix the two ends of the vessels onto sandpaper, which was then folded and placed on the Ustretch system hooks.Engineered rings; engineered vessels; and controls of human saphenous vein and cadaver femoral artery were histologically analyzed to determine tissue structure, ECM content and ECM organization. Tissues were processed in paraffin. Individual rings and 3-ring vessels with and without Alloderm were fixed in formalin for 48 h. Samples were stored in 70% ethanol in 5 °C until dehydrated. Samples were dehydrated in graduations of 70% to 100% ethanol over 12 h and then embedded into paraffin blocks. Hematoxylin and eosin (H&E), Masson’s Trichrome, and Picrosirius red stains were conducted on all ring groups and Alloderm donuts. H&E revealed cellular and extracellular matrix organization. DAPI stain was used to determine cellularity. Masson’s Trichrome and Picrosirius red stains showed collagen organization and total content in the rings and Alloderm donuts. Collagen quantification for red and blue stained collagen from picrosirius red and trichome, respectively, were quantified as a percentage of total cross-sectional area using ImageJ.Picrosirius red stained samples of rings and Alloderm donuts were observed under polarized light to determine collagen maturity of each sample. Birefringence images were captured using an Axiovert 200 microscope . Mature, thicker collagen fibers appear orange and red under polarized light. Immature, thinner collagen fibers appear yellow and green under polarized light. Polarized light images were quantified for percent cross-sectional area of red, yellow and green fibers using ImageJ.The hemodynamic capabilities of the engineered vessels were assessed by burst pressure testing. Burst pressure gives an indication of the maximum pressure the ECM-integrated BEBVs can withstand. Alloderm-integrated vessels were subjected to pulsatile flow with cell culture media in a custom-made bioreactor with a peristaltic pump , a glass media reservoir, polymer tubing, a custom-made bioreactor chamber, and 3D printed vessel holders. Vessels secured onto 3D printed vessel holders using VetBond. Alloderm vessels (n = 5) were subjected to increasing fluid pressure until failure.Suture retention tests were conducted to examine the graft’s ability to mechanically retain a suture placed using standard surgical technique. These tests were conducted using the UStretch system. Engineered vessels with (n = 5) and without Alloderm (n = 5) were tested following a 7 day culture period after ring stacking. Sutures sized 6–0 proline were sutured through the bottom end of the vessel and then fixed to the bottom hook of the UStretch system using sandpaper and gorilla glue. The top stationary hook on the Ustretch system held the engineered vessels fixed in place using VetBond and sandpaper. The suture was pulled at a strain rate of 0.4 mm/min until the failure. Force output during the duration of the test was recorded and plotted versus displacement.To test the thrombogenicity of the engineered vessels, vessels were incubated with fresh human platelets for 24 h in culture. The human platelets were donated by the Henry Ford Hospital System Blood Bank . Following the 24 h platelet culture, vessels were removed from the platelet solution, formalin fixed for 24 h, dehydrated, paraffin embedded, and sectioned. Platelet adherence to the vessel was assayed by immunostaining using CD41 platelet antibody. The CD41 antibody developed by Rockefeller University was obtained from the Developmental Studies Hybridoma Bank, created by the NICHD of the NIH and maintained at The University of Iowa, Department of Biology, Iowa City, IA 52242. Controls consisted of platelets embedded in fibrin hydrogel.Statistical analyses were conducted using SPSS . Results were presented as means with standard error of means. One-way ANOVA were performed to compare material properties determined from circumferential tensile testing of rings and vessels. Tukey B post-hoc test was used to determine significance between groups. Student’s t-test was performed to compare engineered vessels with and without Alloderm for longitudinal tensile testing, suture retention and burst pressure comparisons. An independent sample t-test was used to compare material properties of the 4-week culture rings to newly formed rings. The alpha level was set to 0.05.30 as depicted in Fig. 31. The human dermal fibroblasts were able to infiltrate the Alloderm material once seeded. Alloderm did not hinder ring formation and integrated into the lumen side of the ring structures and vessels.The Alloderm decellularized dermis was incorporated into our tissue engineered vessel protocolCircumferential ring tensile mechanics significantly improved with inclusion of Alloderm in the rings and vessels. Average stress–strain curves for rings without Alloderm, rings with Alloderm and Alloderm donuts are shown in Fig. Engineered vessel tensile mechanics significantly improved with inclusion of Alloderm. Average stress–strain curves for rings without Alloderm, rings with Alloderm and Alloderm donuts are shown in Fig. Longitudinal tensile mechanics representing strength along the length of the vessels was not significantly different in vessels without Alloderm compared to vessels with Alloderm Fig. , Table 3The force required to strain the engineered rings, engineered vessels and Alloderm alone to failure (Supplemental Fig. Histological analysis of rings provided pertinent information on cellular and ECM protein content and organization in the engineered tissue. Vessel histology showed cellular and ECM organization across the multi-ring structure. Cross-sectional ring samples were stained with multiple stains. Hematoxylin and eosin was used to visualize overall cellular structure by staining nuclei deep purple and cytoplasm and extracellular matrix pink. Masson’s Trichrome and Picrosirius red stains were used to visualize ECM content and organization, by staining collagen blue and red, respectively. DAPI stains were used to clearly demarcate cell density and location.In the standard rings Fig. a–c, fibrLongitudinal cross sections of vessels with and without Alloderm stained for H&E Fig. m,n showeDAPI fluorescent stains of cell nuclei in Alloderm rings showed the organization of the cells along the outer diameter of the rings Fig. . In compPolarized light images of a Picrosirius red stained standard ring, Alloderm ring and Alloderm alone Fig.  allowed No significant differences were found between vessels with and without Alloderm for suture retention Fig. . AverageTo test long-term viability, Alloderm rings were cultured for 4 weeks and mechanically tested Fig. . Alloder32. Hence, the 5 cm long vessel built shows clinical feasibility of our adventitia vessels.A 5 cm long vessel was fabricated Fig.  to demonHuman umbilical vein endothelial cells were successfully seeded into Alloderm vessels Fig. . FormatiTo test thrombogenicity, Alloderm rings were submerged in a fresh human platelet concentrate for 24 h. Negative CD41 anti-platelet antibody stains of the Alloderm rings indicated no platelet adherence Fig. . The conThe Alloderm ECM resulted in the ideal material for adding strength to tissue engineered blood vessels. Given the Alloderm’s pliability and strength, it easily integrated into the aggregating ring structures while concurrently offering sufficient support and strength for the final tissue. The Alloderm ECM organized into the lumen side of the ring and was lined by the fibrin gel and cells on the outer edge. This organization allowed the Alloderm to serve as the main component to counteract forces exerted on the tissue while the cells on the outer edge provided elasticity. This observation was supported by the tensile results showing two main failure points- first, of the stiffer Alloderm material and then, of the more elastic cellular component. Interestingly, vessels with the Alloderm material showed increased collagen content and encouraged collagen deposition by the cells as seen in the additional collagen lining the cells. Additionally, cell nuclei were seen located in the fibrin gel and Alloderm, which indicates that the extracellular matrix encouraged cell migration and infiltration.12. The other important parameter for clinical application is the burst pressure. There was a significant difference in burst pressure with the addition of the Alloderm—however, the burst pressure needs further improvement in order to meet human blood pressure values. Our lab is currently testing methods to improve burst pressure in our vessels with promising preliminary results, which is the focus of an upcoming follow-up study. Nevertheless, the current burst pressure strength of 51.3 ± 2.19 mmHg of the Alloderm vessels is encouraging as it approaches human diastolic blood pressure values.Inclusion of the Alloderm into the engineered rings significantly improved circumferential tensile mechanics compared to standard rings. This is due to the significant increase in the load-bearing collagen extracellular matrix protein provided by the Alloderm. These results are quite encouraging to progress towards clinical application, since the incorporation of the Alloderm elevated the engineered vessels’ tensile strength to 1500 ± 334 kPa, which allows the engineered vessel to meet the comparative native adventitia tensile strength of 1430 ± 604 kPaInterestingly, Alloderm rings exhibited a lower ultimate tensile strength and failure strength than Alloderm alone. This is due to the differences in the cross-sectional area of each group. Stress is calculated as the force divided by the cross-sectional area, meaning that larger cross-sectional areas result in lower apparent stress. The rings have an inherent larger cross-sectional area due to the additional thickness of the cells and hydrogel compared to the Alloderm alone. Thus, the thicker the tissue, the larger the cross-sectional area and thus the smaller the calculated stress for a given force applied. This effect directly correlates to the parameter of strength which is determined from the stress–strain curve, as stress is a normalized factor, however, in cases such as this, force needed to cause tissue failure also provides useful information.2. Regardless, the current study in our lab to improve burst pressure will concurrently strengthen the vessels in the longitudinal direction. Suture retention was not significantly different between standard engineered vessels and Alloderm vessels likely because suture retention relies on longitudinal structural components, similar to burst pressure strength. Hence, since burst pressure was not significantly different, it is not surprising that suture retention strength followed a similar trend.In the longitudinal direction, no significant differences were observed in forces associated with the elastic modulus and ultimate tensile strength between standard vessels and Alloderm rings, meaning that the addition of the Alloderm did not affect longitudinal vessel mechanics. Longitudinal strength of the engineered vessels with or with Alloderm could be improved. However, in vivo the vessels would not be subjected to major forces in that direction. Also, it has been shown that engineered vessels after implantation are remodeled with endogenous cell engraftment which further strengthens the tissue in all directionsThe 4-week long cultured Alloderm rings exhibited retainment of mechanical properties over time. Failure strength 2 correlates with the strength of the fibrin gel in the rings. The increase in failure strength 2 in Alloderm rings indicates increased ECM deposition around the rings by the cells. The biological environment promotes tissue growth and ECM deposition, hence the engineered vessels will be further strengthened upon implantation in the future. Rings were chosen in this test because any potential mechanical changes over time would not exhibit a difference in rings compared to vessels.29.The 5 cm long vessel built is capable of accommodating common repair of vessels such as the popliteal artery, femoral artery and iliac artery. In practice, any length vessel can be built using our methods by simply adding additional rings to the vessel, thus allowing for our methods to accommodate any vessel repair length needed. Moreover, vessel lumen can easily be modified by changing dimensions of the posts the vascular rings are fabricated around, furthering applicability of our vessels to accommodate repair of vessels of differing lumen sizes from small-diameter to larger diameter grafts, as was demonstrated in our previous work of fabricating vessels of lumen size 6, 10 and 20 mm33. Thus, demonstration of successful endothelialization of our Alloderm-integrated adventitia vessels provides further evidence of clinical applicability. The negative platelet adhesion test results further support patency of our engineered vessels, even with the inclusion of the Alloderm material. As one of the primary steps in coagulation, which can lead to vessel occlusion, the inherent characteristic of the adventitia vessels to not preferentially adhere platelets is advantageous.Successful endothelialization of the vessels show that the vessels readily support formation of an intima, which is pertinent for establishing proper hemodynamics. Endothelialization of grafts has shown to aid in increased patency rates38. Alloderm has been used to in the clinic since 1994 and continues to be used today. The primary findings from the in vivo studies and clinical data are that Alloderm promotes neovascularization and fibroblast infiltration; and reduces inflammation and fibrosis compared to controls. Clinically, Alloderm has shown to integrate well into host tissue and has not, in some studies, shown any safety concerns in a 5-year follow-up. These positive attributes of Alloderm in vivo show promise for our Alloderm-integrated vessels to perform advantageously once implanted. Animal studies are planned in the near future to fully test our Alloderm vessels and determine outcomes following implantation.In regard to in vivo performance, Alloderm has extensively previously been studied for its effects in vivo and in clinical application in human patientsHere, we demonstrate the incorporation of commercially available decellularized extracellular matrix Alloderm to significantly improve the mechanical properties of our engineered biological vascular grafts, a pre-requisite for meaningful clinical utility. Additionally, the added ECM advantageously increased collagen content, improved ECM organization, increased mature collagen content, encouraged cell engraftment, and demonstrated the capability of endothelialization. Our ongoing work on methods to improve burst pressure strength currently shows promising preliminary results, further increasing its relevance for prospective patient applications.Supplementary Tables.Supplementary Figure.Supplementary Video 1.


Background and Objective: Few studies have explored the relationship between malnutrition measured by the Geriatric Nutritional Risk Index (GNRI) and cognitive performance. This study aimed to investigate the association of malnutrition with cognitive function in the Chinese population.Methods: It was a prospective longitudinal study and used three waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) data in 2011–2012, 2014, and 2017–2018. Participants aged 60 years or older without mental illness and cerebrovascular diseases were eligible. The GNRI was used to assess nutritional status as follows: normal nutrition (a GNRI > 98), mild malnutrition (92 ≤ a GNRI ≤ 98), and moderate-to-severe malnutrition (a GNRI < 92). Cognitive performance was evaluated by the Mini-Mental State Examination (MMSE) scores. The relationship between the GNRI and cognitive function was analyzed using a linear mixed-effects model.Results: A total of 1,632 subjects were analyzed, including 741 males and 891 females. Of these, 65.0, 19.4, and 15.6% of subjects were at normal nutritional status, mild, and moderate-to-severe malnutrition, respectively. After adjusting for potential confounders, participants under mild and moderate-to-severe malnutrition status have a lower MMSE score , compared with those having normal nutrition. Also, there was a linear trend in the association of malnutrition risk with cognitive function in the total population [β (95% CI): –0.74 ]. However, a significant association of malnutrition with cognitive function was observed only among illiterate females aged above 90 years.Conclusion: This study suggested that there was a significant relationship between the GNRI and cognitive function in the Chinese elderly. Furthermore, subjects with more serious malnutrition have a worse cognitive function, especially in the oldest illiterate females. Clinicians should put more emphasis on assessing the nutritional and cognitive status of the elderly to timely intervene and prevent cognitive impairment. It is estimated that more than 1.5 billion people will be aged 65 or older by 2050, accounting for 16% of the total population. Consequently, further attention should be paid to the physical and mental health of the elderly . With thMeanwhile, mild cognitive impairment (MCI), as a transitional state between normal aging and dementia, has affected 10–15% of the population aged 65 and above  and gradPrevious studies have demonstrated that nutritional status played a significant role in the progression of cognitive impairment in older patients with dementia or Alzheimer’s disease (AD) . Recent Accordingly, our study aimed to further investigate the relationship of malnutrition, measured by the GNRI, and cognitive function in the Chinese elderly, based on the three waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) data in 2011–2012, 2014, and 2017–2018.Data were based on the CLHLS study. The CLHLS is a nationwide community-based prospective longitudinal study, aiming to investigate health status and factors influencing longevity in the Chinese elderly. Its baseline survey began in 1998, and seven follow-up survey waves were conducted in 2000, 2002, 2005, 2008–2009, 2011–2012, 2014, and 2017–2018, respectively . To obtaIn addition, a biomedical in-depth CLHLS study was performed in the CLHLS of waves 2008–2009, 2011–2012, and 2014 in sequence. During the in-depth study, physical examinations and almost 30 biomarkers in blood and urine samples were collected by the trained medical staff of the Chinese Center for Disease Control and Prevention local network. More details of the in-depth CLHLS study have been published elsewhere . The CLHIn this study, we used three waves of the CLHLS data in 2011–2012, 2014, and 2017–2018. The inclusion criteria were as follows: participants aged 60 years or older; and participants with complete baseline information of the GNRI and Mini-Mental State Examination (MMSE) score. The exclusion criteria were as follows: participants with missing data in covariates; and participants with a history of intracranial tumor, craniocerebral injury, acute infection, mental illness, and cerebrovascular diseases, which were self-reported. Eventually, 1,632 eligible participants were included. The detailed information is presented in The baseline data were collected using a standardized questionnaire in a home-based interview by trained investigators in 2011–2012 and 2014 waves. The information included (1) sociodemographic characteristics such as age, sex , ethnicity (Han/other), residence , marital status (married/other), education level (no schooling/some schooling), and living alone (yes/no), (2) lifestyle-related variables such as current smoking status (yes/no), drinking status (yes/no), and regular exercising (yes/no), and (3) health status involving a self-reported history of heart disease (yes/no), hypertension (yes/no), diabetes (yes/no), and arthritis (yes/no). Participants were divided into three age groups: 60–79 years, 80–89 years, and ≥90 years.The participants were asked to report their food intake frequency of last month of vegetables, meat, eggs, and fish. The intake frequencies of meat, fish, and eggs were recorded as “almost every day,” “occasionally,” or “rarely or never.” While for vegetables, the intake frequency was “almost every day,” “almost every day except in winter,” “occasionally,” and “rarely or never” . In the After the interview, the anthropometric measurements were carried out to obtain height (in meters) and weight (in kilograms). All measurements were carried out three times, and the average values were recorded. Body mass index (BMI) was calculated as weight divided by the square of height.Serum albumin was measured by trained personnel using an automatic biochemistry analyzer  at the central laboratory at the Capital Medical University in Beijing.In this study, the GNRI was used to evaluate nutritional status. The GNRI is calculated by albumin and weight loss as follows: GNRI = [1.489 × serum albumin (g/L)] + [41.7 × ] . Weight In each wave of the CLHLS, cognitive function was assessed by the Chinese version of MMSE, which was adapted from the international version that was proposed by 25, P75), whereas categorical variables were expressed as frequencies (percentages). The distributions of baseline characteristics were compared by one-way ANOVA, Kruskal–Wallis non-parametric test, and χ2 test across the normal, mild malnutrition, and moderate-to-severe malnutrition groups. For the primary analysis, a linear mixed-effects model was employed to estimate the effects of malnutrition on cognitive function, adjusting for age, sex, ethnicity, residence, marital status, education, living alone, regular exercising, smoking, drinking, history of heart diseases, diabetes, hypertension, and arthritis, BADL disability, and the frequencies of meat, fish, eggs, and vegetables. In the linear mixed-effects model, the MMSE scores from waves 2011–2012, 2014, and 2017–2018 were response variables, and malnutrition assessed by the GNRI was an independent variable. Furthermore, the linear mixed-effects model was stratified by sex, age, and education level. Four sensitivity analyses were conducted. First, the GNRI as a continuous variable was considered as an independent variable in the linear mixed-effects model. Second, serum albumin and BMI were used to construct linear mixed-effects models, respectively. Third, the mediation analysis was used to examine whether the association between malnutrition and cognitive impairment was mediated by hypertension and diabetes. Finally, we imputed the missing covariates using the R software package “mice” to evaluate the influence of missing covariates on the results. Two-tailed P < 0.05 was considered to be statistically significant, and all analyses were conducted using SAS 9.4 .Continuous variables with normal distribution were presented as means ± SD. Non-normal variables were reported as median (PP < 0.001). Also, subjects who have been married (P < 0.001), had regular exercises (P < 0.001), and ever attended school (P < 0.001) were less likely to be malnourished. Additionally, in contrast with normal nutritional group, people under malnutrition status tended to have BADL disability (P < 0.001), rare or never eat meat (P = 0.001), fish (P = 0.007), eggs (P = 0.015), and vegetables (P < 0.001). However, ethnicity, residence, living alone, and history of heart diseases, diabetes, and arthritis were not significantly different across the three groups.Among 1,632 subjects, the average age was 85.57 ± 12.35 years old, and 54.6% of subjects were females. The proportion of participants in the normal nutrition, mild malnutrition, and moderate-to-severe malnutrition groups was 65.0, 19.4, and 15.6%, respectively. As shown in P = 0.007 and P < 0.001, respectively). Compared with the normal nutrition group, those with mild and moderate-to-severe malnutrition have a lower MMSE score of 0.95 and 1.39 points . Moreover, the MMSE score has shown a significant linear downward trend with increasing malnutrition degrees (adjusted P for trend < 0.001).P = 0.196 and P = 0.514, respectively). While for female subjects, there was a negative association of mild and moderate-to-severe malnutrition with cognitive function regardless of adjusting covariates or not . A significant trend of a cognitive decline with increasing malnutrition degrees was observed in females (adjusted P for trend < 0.001) but not in males (adjusted P for trend = 0.289).P = 0.057 and P = 0.821, respectively) and 80–89 years . While among the elderly above 90 years old, a significant association was observed between mild and moderate-to-severe malnutrition and cognitive function . Moreover, a linear trend in the association of malnutrition risk with cognitive performance was also found in individuals aged 90 years and above (adjusted P for trend < 0.001).The association between malnutrition and cognitive function stratified by age is presented in P = 0.004 and 0.007 for mild and moderate-to-severe malnutrition, respectively; adjusted P for trend = 0.002), while the association disappeared among the elderly who ever attended school . Namely, subjects with a higher GNRI or serum albumin have a better cognitive function, while BMI was not associated with cognitive decline (adjusted P = 0.499). In the mediation analysis, as shown in P = 0.024) and moderate-to-severe (adjusted P = 0.004) malnutrition and cognitive function in the complete dataset.As shown in A longitudinal study of 1,632 Chinese elderly was used to explore the relationship between malnutrition and cognitive function. We found that malnutrition was associated with cognitive function. Furthermore, subjects with more serious malnutrition have a poorer cognitive performance, especially in illiterate females and the oldest elderly. With increasing degrees of malnutrition, the cognitive function has shown a worsening trend.Participants were classified into different nutrition status groups according to the GNRI. Notably, 19.4% of participants were under mild malnutrition risk, and 15.6% were moderate-to-severe malnourished. People with malnutrition status were older than those with well-nourished status. This result is in line with studies using alternative methods, such as MNA or MNA-SF, to assess the elderly malnutrition status . With thSerum albumin, as an indicator to assess nutritional status and inflammation level, has been used to predict adverse clinical outcomes . Recent In this study, a strong association between malnutrition and cognitive function was found among individuals aged 90 years and above. We speculated that there was a similar increasing trend of malnutrition risk and cognitive decline with aging, which caused this association. On the one hand, older age has been identified as a risk factor of malnutrition . Also, pIn addition, a significant association also appeared in female individuals and participants without attending school. A possible explanation might be due to socioeconomic disadvantages, lacking education, and worse financial situation. As reported earlier, females were more likely to have a higher prevalence of malnutrition and cognitive impairment . MeanwhiTherefore, although the underlying mechanism of the relationship between malnutrition and cognitive function is not clear until present, the GNRI defined that using serum albumin and weight loss has been validated in exploring the association of malnutrition with cognition function in this study. Researchers should make full use of the GNRI, rather than a single biomarker, in further malnutrition-related studies.Our study has some strengths. First, because the CLHLS is a representative study in the Chinese elderly, the conclusion of our current study was more credible and reproducible. Second, compared with the previous study, we used the CLHLS, a longitudinal cohort study, to examine the association between malnutrition and cognitive function, which makes it easier to interpret the causal link between malnutrition and cognitive function. Finally, to our knowledge, the GNRI was rarely used to evaluate the relationship between malnutrition and cognitive function, particularly in the Chinese elderly. Compared to another single indictor, the GNRI has been considered as a reliable comprehensive tool for assessing malnutrition in the elderly. Thus, our study could provide solid evidence on the association of the GNRI with cognitive impairment, which is beneficial for delaying or preventing the occurrence and progression of cognitive impairment. However, this study had some limitations. First, since the CLHLS was designed for the oldest-old Chinese, generalizing the results to other populations should be cautioned. Second, although we collected confounding factors such as smoking, drinking, food intake frequency, hypertension, and history of diabetes, it may lead to a potential recall bias as some of them were self-reported. Third, since biomarkers were assayed for once in the random sample, the changes over time of biomarkers failed to be considered in this study. Finally, this study was enriched for octogenarians and nonagenarians, who might be healthier and less likely to suffer from malnutrition and cognitive impairment. Therefore, this study might underestimate the association of malnutrition with cognitive function.A significant association of malnutrition measured by the GNRI with cognitive performance was observed among the Chinese elderly. Subjects with malnutrition have a poorer cognitive function, especially in illiterate females and the oldest elderly. Furthermore, the cognitive function was worse with malnutrition aggravating. Accordingly, the GNRI should be used broadly to evaluate and improve the nutritional status of the targeted elderly population. Moreover, improving early detection of malnutrition and managing routine nutritional surveillance are crucial for the elderly to prevent cognitive impairment.https://sites.duke.edu/centerforaging/programs/chinese-longitudinal-healthy-longevity-survey-clhls/surveydocumentation/questionnaires/ and the full datasets used in this analysis are available at https://opendata.pku.edu.cn/dataverse/CHADS.The datasets presented in this study can be found in online repositories: The CLHLS questionnaires are available at This study was approved by the Institutional Review Board, Duke University (Pro00062871), and the Biomedical Ethics Committee, Peking University (IRB00001052–13074). The patients/participants provided their written informed consent to participate in this study.YC: conceptualization, formal analysis, and supervision. WL and YC: methodology, review, and editing. BS and YZ: writing–original draft preparation. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The paper critically reconstructs the crowd psychological heritage in phenomenological and social science emotion research. It shows how the founding figures of phenomenology and sociology uncritically adopted Le Bon’s crowd psychological imagery as well as what I suggest calling the disease model of emotion transfer. Against this background, it can be examined how Le Bon’s understanding of emotional contagion as an automatic, involuntary, and uncontrollable mechanism has remained a dominant force in emotion research until today. However, a closer look at phenomenological descriptions and empirical investigations of how emotion’s spread shows that there is little evidence supporting Le Bon’s crowd psychological framework. Thus, I suggest that the disease model should be dismissed in favor of more plausible approaches to interpersonal emotion dynamics. The aim of this paper is to critically reconstruct the heritage of Le Bon’s crowd psychological framework in phenomenological and social science research on emotional processes in gatherings of various sizes. This heritage mainly consists of two interconnected features: First, the crowd psychological imagery of the crowd as an animalistic, filthy, and violent social unit, which implies that crowds are beyond rational control and thus of dubious moral status and low social value. Second, the influence of what I suggest calling the disease model of emotion transfer, implying that emotions are transmitted between individuals beyond conscious awareness and control.This paper applies a double strategy: On the one hand, I show how major figures in early sociology, classic phenomenology, and more recent social psychology adopted Le Bon’s crowd psychological framework – either rather uncritically or without awareness thereof. It is impossible, of course, to investigate the entire history of 20th and 21st century emotion research to prove this point, not least within one research paper. However, by focusing on three paradigmatic contexts which are crucial for the development of sociology, phenomenology, and social psychology respectively, and which are prominent sites of Le Bon’s influence, I am confident that the paper can provide some plausibility for this first conclusion.On the other hand, I support two claims: First, the concept of the “crowd,” as Le Bon defined it, does not correspond to an actual phenomenon. Second, the concept of “emotional contagion,” again as defined by Le Bon, misconceives what is going on when individuals emotionally affect each other. An extensive defense of those claims goes beyond the scope of one paper. But luckily, the paper can build on existing literature. At least two book-length studies have argued for the implausibility of Le Bon’s notion of the crowd.I proceed in four steps. First, I present an account of how crowd psychology was founded at the end of the 19th century by Le Bon. This is crucial for understanding the ideological background from which the crowd psychological framework emerged and how this informed the imagery on which it was based. Second, the paper looks at the founding figures of French and German sociology to show how they related to the crowd psychological framework. For the French context, I briefly reconstruct the alternative between the frameworks of Durkheim and Tarde as potential foundations of French sociology, which was quickly decided in favor of Durkheim. Then, I show how Simmel and Weber laid the foundations of German sociology by excluding the issue of the crowd from the subject area of sociological research. Third, I look at Scheler as one of the founding fathers of phenomenology and arguably the most influential voice concerning the understanding of emotions and particularly their potential sharedness within classic phenomenology. I show how Scheler’s seminal understanding of emotional contagion and its distinction from other forms of emotional sharedness is strongly influenced by the crowd psychological framework. Finally, I turn to the mimicry model of emotional contagion, which was introduced by Hatfield, Cacioppo, and Rapson and remains prominent in current social psychological emotion research. This allows me to examine how a crowd psychological understanding of emotional contagion as an automatic, involuntary, and uncontrollable mechanism remains a dominant force in today’s emotion research, even when that heritage is not explicitly noted as such.Sections 2 and 3 provide more of a historical reconstruction of the crowd psychological framework with its imagery of the crowd and the disease model of emotion transfer. Sections 4 and 5 offer a more systematic discussion of the issues at hand. Together they lead to my concluding recommendation that we should actively avoid relapsing into the imagery of the crowd and the disease model of emotion spreading for the benefit of more plausible approaches to the study of social groups and emotional dynamics in interpersonal contexts.One final introductory remark: The following investigation is based on an examination of the original German and French sources. In some instances, English editions became available only long after the period investigated here. In other instances, English translations hide the crowd psychological traces, and more importantly, conceal the problematic ideological import of crowd psychology. Thus, one needs to go back to the original sources to trace the influence of the crowd psychological framework.Les Origines de la France Contemporaine.This section offers a brief history of how crowd psychology originated from France at the end of the 19th century. The founders of crowd psychology are Gabriel Tarde and, most importantly, Gustave Le Bon. Both rely on Hippolyte Taine’s Psychologie des Foules , is part of a trilogy: One year prior to its publication, Le Bon published Les Lois Psychologiques de l’Évolution des Peuples (translated as The Psychology of Peoples), one year later Psychologie du Socialisme .As we will see in the following section, Tarde’s goals were primarily theoretical – aiming at a methodological foundation of sociological research – which makes it plausible to detach his work from the ideological connotations of its historical origin. By contrast, Le Bon not only embraced Taine’s political orientation, but offered a much more radicalized political outlook. Le Bon was an outspoken elitist and racist. He was convinced that each “race” has a particular “soul” and that those souls stand in a natural hierarchy. Analogously, he claims that there is a natural hierarchy and order in each society according to which some are born to rule and others are born to follow. Le Bon’s most well-known book, The Crowd is embedded within this trilogy. In the French original the first two sentences of Psychologie des Foules read as follows: “Notre précédent ouvrage a été consacré à décrire l’âme des races. Nous allons étudier maintenant l’âme des foules.”The Psychology of Peoples) and starts with the innocuous second sentence, “The following work is devoted to an account of the characteristics of crowds.”The Crowd makes the connection clear. It summarizes Le Bon’s racist claim from the previous book, according to which each “race” has its own “soul” (l’âme), that is, certain essential features “which heredity endows the individuals of a race.”The Psychology of Peoples, Le Bon advocates a hierarchy of “races” based on biological determinism.The English edition hides how The Crowd, Le Bon asserts that he addresses the issue of the crowd “in a purely scientific manner.”In the preface of foule.” To describe a gathering as a “foule” already points towards evaluating it as ignorant and potentially out of control. In everyday language, the word is used for spectators of a football match or a group of protesters, but not for a theatre audience or a group of law enforcement officials. The same can be said for the German term “Masse,” which is used as the translation of “foule” in the German edition of Le Bon’s work and sparked the debate under the label “Massenpsychologie” (see the following two sections). Note, however, that Le Bon also considers juries or parliaments as examples of crowds.governo stretto over governo largo, one could say with Machiavelli). Thus, he saw participatory institutions like parliaments and juries as signs of a decay from the natural order. Building on the connotations of the term “foule” in everyday language, the imagery of Le Bon’s text focuses on the connection of the crowd with animality, barbarism, and filthiness. He characterizes crowds as irrational and irresponsible, displaying a propensity to madness and violence.12From the outset, Le Bon aims at the slandering and maligning of the “crowd,” which is his term for the alleged soul of the plebs. This is already indicated by the choice of the term “The Crowd Le Bon defines what he considers “the mind of the crowd.” This contains the substance of Le Bon’s theory. Le Bon’s approach is crowd psychological in the strict sense of the word: He aims at a psychological understanding of the crowd. According to Le Bon’s definition, the crowd is a social unity with a mind of its own:law of the mental unity of crowds.”13In its ordinary sense the word ‘crowd’ means a gathering of individuals of whatever nationality, profession, or sex, and whatever be that chances that have brought them together. From the psychological point of view the expression ‘crowd’ assumes quite a different signification. Under certain given circumstances, and only under those circumstances, an agglomeration of men presents new characteristics very different from those of the individuals composing it. The sentiments and ideas of all the persons in the gathering take one and the same direction, and their conscious personality vanishes. A collective mind is formed, doubtless transitory, but presenting very clearly defined characteristics. The gathering has thus become what, in the absence of a better expression, I will call an organised crowd, or, if the term is considered preferable, a psychological crowd. It forms a single being, and is subjected to the In chapter 1 of As this definition makes clear, not all gatherings are crowds in Le Bon’s psychological sense, but only those that are constituted by this supposed crowd mind. And crowds are not restricted to large gatherings, also small groups can be crowds in Le Bon’s sense. Becoming part of a crowd implies a loss of individuality and a fusion into the collective mind of the crowd. This “collective mind […] is entirely dominated by unconscious elements, and is subject to a peculiar collective logic.”contagion is meant to invoke the idea of an infectious disease. Le Bon defines contagion as the instance of a sentiment, thought, or wish being transmitted from one person to another without an awareness of that transfer and without any possibility of conscious control.19Le Bon lists three mechanisms that lead to the emergence of this supposed crowd mind. First, the crowd is governed by sentiment instead of reason, with the sentiment of the crowd being so powerful that it overrides individual reasoning.Hopefully, the remarks in this section have been sufficient to expose the racist and elitist origins of Le Bon’s thought and the platitude of his argument. The following sections show how Le Bon nevertheless managed to considerably influence 20th century thought.The Laws of Imitation, which was published in 1890, five years prior to The Crowd.Massenpsychologie was almost exclusively based on Le Bon’s writing.23As I already mentioned in the previous section, Le Bon’s work on the crowd was influenced by Gabriel Tarde’s counter-imitation.”Les Règles de la méthode sociologique .29In contrast to Le Bon’s ideological aims of maligning and controlling the supposedly maddening crowd, the objective of Tarde’s work was to found sociology as a scientific discipline. He wanted to present the general laws of the social that apply to all societies.Soziologie: Untersuchungen über die Formen der Vergesellschaftung .In contrast to the French context, where the Durkheimian holistic understanding of the social meant that crowd psychology was contested by a more plausible framework, the methodological individualism of German sociology entailed that the topic of the alleged crowd was excluded from sociological concerns. This had the odd consequence that the crowd psychological framework was tacitly accepted by sociologists as the appropriate approach for the investigation of large gatherings. A first instance of this argumentative move can be found in Simmel’s Economy and Society, another classic of German sociology.social action. Action is defined here as behavior to which the acting individual attaches a subjective meaning. Social action implies that this meaning takes the behavior of others into account.social action and action conditioned by crowds, and thus, between the subject matters of sociology and crowd psychology. At the same time, Weber acknowledges that it might be difficult or maybe impossible to empirically draw this distinction.38The argumentative move to delineate the subject matter of sociology by distinguishing it from the issue of crowd psychology is even more pronounced in Max Weber’s Gemeinschaft) and society (Gesellschaft), which was introduced by Ferdinand Tönnies (another founding father of German sociology) and supplemented it with the notion of the crowd (Masse) from crowd psychology.Mitgefühl).Around the same time as Simmel and Weber laid the groundwork for German sociology, Max Scheler set the stage for the way in which classic phenomenology approached sociality. Most importantly, Scheler adopted the distinction of community .Formalism in Ethics and Non-Formal Ethics of Values appeared, with a second volume following in 1916.The Nature of Sympathy saw a second edition with the title Wesen und Formen der Sympathie .Formalism in Ethics.But before we dive into the content of Scheler’s work, it is important to consider the publication history of the relevant texts. The book which is known to English-speaking readers under the title Formalism in Ethics. His very short definition of the crowd reveals how Scheler follows Le Bon’s imagery:A social unit is constituted (simultaneously) in so-called contagion and involuntary imitation devoid of understanding. Such a unit of animals is called the herd, of men, the mass. With respect to its members, the mass possesses a reality of its own and has its own laws of effectiveness.”45Scheler introduces his taxonomy of possible social units towards the end of The Nature of Sympathy Scheler states that, “man becomes more of an animal by associating himself with the crowd.”Masse) is constituted by contagion (Ansteckung) and imitation (Nachahmung). As the source for this claim Scheler refers to his own work The Nature of Sympathy. In the relevant passage from The Nature of Sympathy, Scheler refers to two books by Le Bon, Psychologie des Foules and a book with the title “L’âme révolutionnaire.”Les Lois de l’imitation and Sigmund Freud’s Group Psychology and the Analysis of the Ego from 1921.L’âme révolutionnaire,” Scheler most likely refers to Le Bon’s book La Révolution Française et la Psychologie des Révolutions from 1912.The Crowd) with Scheler’s definition one finds a very strong, almost verbatim correspondence.50Let me dissect this definition sentence by sentence. Beginning from the end, the third sentence alludes to the claim that a crowd has a mind of its own, which is the key systematic claim of Le Bon’s crowd psychological framework. The second sentence draws an analogy between crowds and animal herds, which is also very much in line with Le Bon’s imagery. In a remark added to the second edition of The Nature of Sympathy. Let me prepare an examination of the crucial passages by briefly introducing Scheler’s taxonomy of “fellow-feeling” (Mitgefühl). Scheler begins his characterization by stating that fellow-feeling needs to be distinguished from all behavior which “merely contribute to our apprehending, understanding, and, in general reproducing  the experiences of others, including their states of feeling.”Nachfühlen) an other’s emotion is a precondition and a component of fellow-feeling, but not in itself a form of fellow-feeling.das unmittelbare Mitfühlen); “fellow-feeling ‘about something’” (Mitgefühl an Etwas); and “mere emotional infection” (bloße Gefühlsansteckung).Einsfühlung), but this does not need to concern us here.Miteinanderfühlen), is defined as two or more individuals sharing the same feeling; there feeling is “one and identical.”intentional reference […] to the other person’s experience.”Gefühlsansteckung). Scheler begins his elaboration on emotional contagion by emphasizing its difference from fellow-feeling. The defining difference is that fellow-feeling presupposes an apprehension of the other’s feeling, whereas contagion is precisely defined by the absence of such an apprehension.The cornerstone of Scheler’s adaptation of crowd psychology is the notion of contagion in Before discussing the distinction of fellow-feeling and contagion further, let me show how Scheler’s description of contagion relates to Le Bon’s definition. Scheler embraces Le Bon’s understanding of emotional contagion as a mechanism that seizes an individual beyond conscious awareness and control: The process is “involuntary” and “unconscious”; in a crowd it happens “like an avalanche,” leading to actions “for which no one acknowledges either the will or the responsibility.”61This analogy of emotion transfer and disease transmission is not only embraced by Scheler, but also by other classic phenomenologists. Classic phenomenologist followed Le Bon in assuming that  the disease model has a very broad applicability. It was taken to apply to all types of affective states, both with a positive and negative valence. Scheler’s examples include mourning, laughter, and joy.suggestion as “the ‘implanting’ of ‘notions,’” which “means that the notion is taken over ‘without any logical reason.’”ideas’ of Bolshevism transmit themselves like pathogenic agents from one individual to another and intrude upon him ‘suggestively.’”What is at stake in the disease model can be made explicit with reference to Edith Stein. Stein, summarizing the common theorizing of her time, discusses An interesting question to ask is how one can distinguish contagion from fellow-feeling. The distinction between fellow-feeling in the narrow sense (fellow-feeling “about something”) and contagion is rather straightforward and unproblematic: The former presupposes an apprehension of the foreign feeling whereas the latter is defined by a lack of such an apprehension. More interesting is the distinction between contagion and feeling-in-common, a distinction that is still highly relevant in contemporary phenomenological accounts of collective emotions. Dan Zahavi, for instance, refers to Scheler when stating that emotional contagion needs to be sharply separated from emotional sharing.We have already encountered the main criterion in the passage from Edith Stein cited in the previous paragraph. In feeling-in-common, the emotion is justified, because it is motivated from within the individual having the emotion and answers to what is demanded by the situation. Consider Scheler’s famous example of the parents grieving over the death of their child.Der Krieg als Gesamterlebnis  from 1916, Scheler describes the German experience of World War I as a case of feeling-in-common.The Nature of Sympathy from 1923, however, he classified the same experience as a case of emotional contagion.This can be exemplified with reference to one of Scheler’s examples. In the text But after all, I think that hidden beneath all the biases and prejudices, Scheler was up to something important. Scheler’s core systematic claim is that emotional contagion is not a form of fellow-feeling and should not be confused with it. According to my view, what is at stake here is the distinction between affective we-experiences and underlying psychological mechanisms.This final section concerns the way in which emotional contagion is conceptualized within current social psychology. In contrast to the early stages of sociology and classic phenomenology, there is no direct reference to Le Bon within this current research field. However, there are similarities to Le Bon’s crowd psychological framework which are worth examining. Moreover, newer developments in the field point towards discarding the remainders of the crowd psychological framework and moving towards better accounts of interpersonal emotion dynamics. Emotional contagion, as the term is used in social psychology, is generally defined as “the tendency to ‘catch’ (experience/express) another person’s emotions.”76chameleon effect, that is the “nonconscious mimicry of the postures, mannerisms, facial expressions, and other behaviour of one’s interaction partners.”82Over the last three decades, the leading paradigm in emotion research was the mimicry-based model of emotional contagion. Indeed, some suggest that it “has almost become a dogma in cognitive science.”Over the last few years, the mimicry-based model has been seriously challenged, both regarding its theoretical plausibility and its empirical support. Two challenges are particularly powerful. First, it seems unlikely that perceiving an emotion always elicits the same emotion in the perceiver. For instance, “the perception of another’s display of anger is likely to trigger fear and submission, not anger.”87Much more could be said about this. But allow me to formulate the following tentative conclusion: On the one hand, the analogy with disease transmission seems to be the key ingredient constituting the persuasiveness of the crowd psychological framework. One might even hypothesize that this analogy is a major factor for the long-lasting acceptance of the mimicry-based model of emotional contagion. On the other hand, the disease model is the core of what is systematically wrong with the crowd psychological framework. Upon closer inspection, it is quite implausible that emotions spread like viruses. Virus infection happens without possible awareness and beyond the possibility of conscious control mechanism. As the Covid-19 pandemic has forcefully shown, it is impossible to notice the moment one is infected, or to resist infection through an act of the will. Only retrospectively one can try to trace the time and source of the infection (through measures like contact tracing). But this is not how emotional spreading works: It might be the case that we often do not notice how our moods and emotions are shaped by the environment. It might even be the case that we are secretly manipulated. And it might take much effort and retrospective reflection to find out about the manipulation and its source. However, our emotional lives are open to such reflection and emotional spreading is not in principle beyond possible awareness and control. All of this suggests that disease transmission is a bad analogy for a proper understanding of interpersonal emotion dynamics.In this paper, I have traced the influence of the crowd psychological framework within phenomenology, sociology, and social psychology. I have done so by examining paradigmatic accounts of key thinkers in each discipline. Moreover, I have shown that the persuasiveness of the crowd psychological framework relies on the analogies of the crowd with a herd of wild animals and of contagion with disease transmission. Now, what recommendation for future research does this paper provide? First, I suggest studying social gatherings free from the imagery of the crowd. This suggestion is neither new nor revolutionary, but still worth reemphasizing.89


Malnutrition is highly prevalent in inflammatory bowel disease (IBD) patients and disproportionately affects those admitted to hospital. Malnutrition is a risk factor for many complications in IBD, including prolonged hospitalization, infection, greater need for surgery, development of venous thromboembolism, post-operative complications, and mortality. Early screening for malnutrition and prompt nutrition intervention if indicated has been shown to prevent or mitigate many of these outlined risk factors. There are many causes of malnutrition in IBD including reduced oral food intake, medications, active inflammation, and prior surgical resections. Hospitalization can further compound pre-existing malnutrition through inappropriate diet restrictions, nil per os (NPO) for endoscopy and imaging, or partial bowel obstruction, resulting in “post-hospital syndrome” after discharge and readmission. The aim of this article is to inform clinicians of the prevalence and consequences of malnutrition in IBD, as well as available screening and assessment tools for diagnosis, and to offer an organized approach to the nutritional care of hospitalized adult IBD patients. Inflammatory bowel disease (IBD) is a chronic debilitating inflammatory disorder of the gastrointestinal tract characterized by a relapsing and remitting course. The etiology of IBD is incompletely understood, but includes an imbalance between pro-inflammatory and anti-inflammatory signaling arising from genetic susceptibility and environmental triggers . The twoIBD is often diagnosed in young adulthood or middle age, resulting in a large burden of disability-adjusted life years that is now improving as more effective treatments become available . AdvanceMalnutrition is a frequently under-recognized complication of IBD despite its high prevalence ranging between 20 and 85% . AlthougIn the case of IBD, malnutrition can result from a number of different mechanisms see  includinSarcopenia is a nutrition-associated disorder characterized by reduced muscle mass and strength. There are multiple contributors to sarcopenia in IBD, including chronic inflammation, malnutrition, and physical inactivity . SarcopeThere is a wealth of data pertaining to malnutrition in hospitalized patients as a whole, and while some IBD-specific data exist, this area is still a growing field of interest. The prevalence of malnutrition is high among patients admitted to hospitals in general, with studies demonstrating a prevalence of up to 45% ,17. A laThere are significant adverse clinical implications of underdiagnosing malnutrition in IBD patients. We summarize the current state of knowledge and make best practice suggestions based on expert opinions that practitioners can readily apply to optimize nutritional and clinical outcomes in hospitalized IBD patients. The primary objective of this article is to serve as an expert narrative review to inform clinicians of the prevalence and consequences of malnutrition in IBD, available screening and assessment tools for diagnosis, and its use during hospitalization, and to offer an organized approach to the nutritional care of hospitalized adult IBD patients. We employed a rigorous search strategy for our narrative review for nutrition interventions . We searMalnutrition in hospitalized patients is associated with prolonged length of stay, higher readmission rates after discharge, greater rates of complications, infections, and increased mortality ,20,21. ASpecific to IBD, malnutrition is disproportionately higher in those admitted to hospitals ,24. MalnPatients with severe IBD frequently have restricted oral intake due to their symptoms. Long-term avoidance of specific foods was reported to be as high as 77% in a recent study and can lead to micronutrient deficiencies even in the absence of weight loss . When IBEvidence suggests that identifying malnutrition and introducing a nutritional intervention can improve outcomes in hospitalized patients as a whole ,31. WhilDefining the malnutrition construct as it applies to IBD remains challenging, largely due to a lack of validated tools for its diagnosis. The prevalence is high, but estimates are variable due to use of different tools. An ideal gold standard would include elements of history, physical examination, anthropometric measurements, laboratory markers, body composition, and assessments of physical and mental functioning. While such a comprehensive assessment would capture the spectrum of malnutrition in IBD, it is not practical and could not be universally applied. In clinical practice and even in research settings, malnutrition in IBD is usually diagnosed using nutritional assessment tools (NAT); however, many of these are not yet comprehensively validated in IBD.Various NAT are available and validated in general medical conditions, including bedside global assessment, bedside muscle measurements, bedside body composition analysis, and cross-sectional measures of body composition. Bedside global assessments include elements of clinical history, diet history , physical examination, and laboratory values. The Subjective Global Assessment (SGA) is one of the most widely used bedside global NAT, and has been well validated in general populations . In IBD,Bedside muscle measurements include hand grip strength (HGS), mid-upper arm circumference (MUAC), and mid-upper arm muscle circumference (MUAMC). HGS has been shown to be an effective, quick, and convenient parameter to predict functional status and muscular health in CD patients compared to healthy controls . HGS corNAT focused on identifying altered body composition include bioelectrical impedance analysis (BIA), which can be conducted at the bedside, or radiologic tools such as dual-energy x-ray absorptiometry (DEXA), computer tomography (CT), and magnetic resonance imaging (MRI). Body composition analysis estimates lean body mass and can be used to determine the presence of sarcopenia. The practical use of DEXA and BIA are limited in a hospital environment due to extra resources including equipment and time, or potential adverse effects such as radiation. Currently, body composition analysis tools are primarily being used for research. While CT and MRI are frequently performed on patients with IBD for assessment of their disease, software for calculations of body composition from such imaging is not universally available. Thus, with resource or time constraints, HGS and MUAC are more portable and easily obtained in a hospital and outpatient environment compared to DEXA or BIA, which require specialized equipment. However, clinicians may not have the tools and time to perform these bedside measurements, which are likely most useful when taken serially.2 or the combined finding of unintentional weight loss with reduced BMI  or reduced fat free mass index (FFMI)  [2. The American Society of Parenteral and Enteral Nutrition (ASPEN) criteria for malnutrition require two or more characteristics including insufficient energy intake, weight loss, loss of muscle mass, loss of subcutaneous fat, and localized or generalized fluid accumulation that may sometimes mask weight loss or diminished functional status as measured by HGS [ESPEN criteria to diagnose malnutrition require either a low BMI of <18.5 kg/mr males) . Fat fred by HGS .2 for females and <17 kg/m2 for males [However, ESPEN and ASPEN criteria may not capture all components of malnutrition in IBD, especially micronutrient deficiencies that may arise due to malabsorption, selective avoidance of food groups, or high losses. Until a gold standard for malnutrition in IBD is created, we recommend that a diagnosis of malnutrition in IBD not require a low BMI nor unintentional weight loss. We suggest if an IBD patient has a minimum of two criteria below, a diagnosis of malnutrition should be considered. These include food restrictions/avoidance, active luminal disease, symptoms of nausea/vomiting/diarrhea/poor appetite beyond one week, unintentional weight loss >5% in 3 months, HGS < 20% percentile based on age/gender, or low FFMI < 15 kg/mor males . These bWhile a formal nutrition assessment in all inpatients would appear to be the optimal approach, this is not feasible due to limited resources. Nutritional screening tools (NST) are rapid and simple evaluation tools that can be completed by any healthcare team member, and even the patient. Screening tools are designed to detect risk for protein and energy malnutrition, and/or predict whether malnutrition is likely to occur under present or future conditions . A positFamiliar and validated NST include the Malnutrition Universal Screening Tool (MUST) and Nutrition Risk Screening (NRS-2002). MUST was initially developed for outpatient settings where serious confounders of the effect of malnutrition are relatively rare . HoweverBoth the NRS-2002 and MUST factor in BMI, amount of weight loss in a specified time, any reduced nutritional intake, and assessment of whether the patient is acutely ill. Unlike MUST, the NRS-2002 incorporates an age adjustment score of ≥70 years old, outlines specific medical conditions to stratify disease severity, and quantifies ranges of reduced food intake in a one-week span. Kondrup et al. outline the specific scoring parameters of these two screening tools . A recenA 2019 systematic review explored various NST used in IBD patients including MUST, NRS-2002, Malnutrition Inflammation Risk Tool (MIRT), and Saskatchewan IBD-Nutrition Risk (SaskIBD-NR tool) . The sysWe recommend that all IBD patients with a new diagnosis, flare, or complication associated with their IBD, including hospitalization, infection and surgery, be screened for malnutrition. Patients with active disease have the highest risk of malnutrition, especially in newly diagnosed IBD . IdentifHospitalized IBD patients screened for risk of malnutrition should have comprehensive nutritional assessments involving a dietitian and a nutritional management plan that is well-developed. Focus groups highlighted that physicians do not screen for malnutrition frequently enough and miss opportunities to intervene early in malnourished IBD patients . Given tNutritional assessment and therapy should be initiated within 24 h of hospital admission in patients assessed as positive for malnutrition risk. Nutrition intervention can consist of one or more of: oral nutritional supplements (ONS), enteral nutrition (EN), peripheral parenteral nutrition (PPN), or central parenteral nutrition (CPN). A proposed algorithm for nutrition support is presented in When safe and feasible, using the oral or enteral route is the preferred method for nutrition support, and oral feeding is preferred to tube feeding. Advantages of using the gut to deliver nutrition support include lower cost, avoidance of intravenous (IV) access related complications, maintenance of epithelial barrier integrity, immune modulation, and effects on the microbiome . ONS areEN is indicated in patients who cannot meet nutritional needs orally but have a sufficiently intact gastrointestinal tract for micro- and macronutrient absorption. Reasons for inadequate oral intake can include malabsorption, active inflammation, diarrhea, anorexia, nausea, vomiting, and abdominal pain. There are several formulations available for enteral  nutrition: polymeric , semi-elemental , and elemental . Standard polymeric formulas are generally recommended as first-line when using EN. However, certain patients who have significant malabsorption or maldigestion can benefit from predigested semi-elemental or elemental formulas. These predigested formulas are higher in osmolarity and are not palatable, and best infused slowly using a feeding tube. In patients who can eat and drink but are not meeting their needs orally, supplemental EN can be used to infuse nutrients slowly at a controlled rate to reduce intolerance related to bolus feeding. Supplemental EN can also be used only overnight in order not to interfere with spontaneous daytime oral intake. Even in patients with CD who present with symptoms of partial bowel obstruction due to intestinal stricture, EN can be used if tolerated, especially if enteral access can be obtained distally to the stricture . Even ifIn patients with CD who present with complications requiring surgery, such as bowel resection for active or fibrostenotic disease or enterocutaneous fistula, internal fistula, or intra-abdominal abscess, there is emerging evidence regarding the benefit of pre-operative EN. In a recent case control study of patients with CD undergoing surgery, Yamamoto et al. demonstrated that compared to no nutritional intervention, a period of two or more weeks of pre-operative EN with an elemental diet was associated with a significant reduction in risk of post-operative wound and anastomotic complications . In anotWhile the usual indication for EN in adult hospitalized patients is to treat malnutrition, there is also evidence for its use as a primary therapy for inflammation in CD. Exclusive enteral nutrition (EEN) is an acceptable first line treatment for pediatric CD . HoweverIt is accepted that malnourished patients who cannot meet nutritional needs by the oral or enteral route should have parenteral nutrition (PN) initiated . PN invoPN implementation should be considered if a patient is meeting less than 50–60% of nutritional needs via the gut . PN has Although guidelines state that there is insufficient high-quality data from well-controlled observational and randomized controlled trials to support the routine use of PPN, clinical experience points to scenarios in which PPN can be utilized to optimize nutrition for hospitalized IBD patients . PPN canIn such a setting of short-term partial restriction of oral intake in a malnourished patient, PPN is a logical intervention. Rapid supplementation via PPN can be expedited as a central line is not required. As delays in central line insertion can take between 24 and 72 h at some institutions, PPN can also serve as a bridge to longer-term CPN.CPN is indicated in patients with significant malabsorption, short bowel syndrome, intestinal obstruction, high output fistula, ileus, intractable vomiting, or uncontrolled severe gastrointestinal bleeding. It is also indicated in those who would benefit from PPN, as described above, but in whom PPN is contraindicated or not feasible, such as those with difficult peripheral IV access, severe malnutrition, fluid restrictions, or metabolic derangements, and those in whom the duration of PN therapy is anticipated to be more than 10–14 days. CPN can also be used in patients who meet criteria for short-term PPN use but happen to have a central line in place already. However, a lumen dedicated for PN use is recommended to reduce infection risk . Even inMalnutrition increases the risk of post-operative complications in patients with IBD, including wound and infectious complications, as well as mortality . Nutritional interventions, both enteral and parenteral, were demonstrated to ameliorate this risk ,69,70,71Post-operative follow-up of IBD patients with intestinal resections is key to reducing the risk of new or progressive malnutrition. As outlined in Poor nutrition, often worsened during hospitalization, is thought to contribute to a phenomenon termed “post-hospital syndrome”, which is a generalized transient vulnerability after hospital discharge which leads to higher morbidity and an increased rate of readmission for the same or other causes . ContinuIn Alberta, Canada, a unique multidisciplinary High Risk Malnutrition Clinic led by gastroenterologists who are also physician nutrition specialists and dietitians was developed specifically to optimize nutrition care of malnourished patients with digestive diseases, including IBD . This unOur narrative review highlighted high-priority areas for consideration in the nutritional management of hospitalized IBD patients see  below. W(A)No gold standard definition of malnutrition in IBD and lack of validated NST and NATThis applies to both hospitalized and community IBD populations. There is a wide range in the reported prevalence of malnutrition in IBD due to a lack of well-validated tools and wide variability in disease location and severity. A set of disease-specific yet encompassing criteria for malnutrition in IBD remains to be determined. Until further high-quality data are available, it is essential that all IBD patients admitted to hospitals be screened for malnutrition utilizing either the NRS-2002 or MUST NST with prompt nutritional interventions if at moderate to high risk of malnutrition.(B)Limited high-quality data for the use/timing of PN, including total versus supplemental, and central versus peripheralWhile there are widely agreed-upon parameters for CPN use and timing, these are based on studies in non-IBD populations, using non-IBD specific nutritional risk assessment tools. Further studies of PN use, including timing and dosing, are warranted. There is a lack of data for when and how PPN can be optimized in patients with IBD. There are critical points early in hospital admission where patients may benefit from PPN as a bridge or supplement to longer-term therapy, but there are no data to guide this use. How IBD patients may benefit from PN requires further research.(C)Paucity of data on the impact of nutritional interventions on hospitalized IBD patientsWhile there is growing literature on the impact of nutrition interventions in improving IBD peri-operative risks, there remains a lack of high-quality studies for benefits of nutrition interventions on other outcomes of interest . Various nutritional therapies including ONS, EN, PPN, supplementary PN, and CPN were explored in this review, and recommendations for the sequenced use of nutritional therapies were provided based on data from other conditions.In summary, we outlined the high prevalence of malnutrition in IBD arising from its unique pathophysiology and the importance of malnutrition screening in all hospitalized IBD patients. We provide an expert opinion on diagnosing malnutrition in IBD that does not require weight loss or low BMI. Finally, we suggest approaches to nutrition therapies for the hospitalized IBD patient. Future prospective studies should prioritize these important areas of research to advance our understanding of how to best treat malnutrition in IBD.