Liver transplantation has become a routine operation in many transplantation centers worldwide. However, liver graft availability fails to meet patient demands. Split liver transplantation (SPLT), which divides a deceased donor liver into 2 partial liver grafts, is a promising strategy for increasing graft availability for transplantation and ameliorating organ shortage to a certain degree. However, the transplantation community has not yet reached a consensus on SPLT because of the variable results. Specifically, SPLT for 2 adult recipients using full right/left hemi-liver grafts is clinically more challenging in terms of surgical technique and potential postoperative complications. Therefore, this review summarizes the current status of SPLT, focusing on the transplantation of adult recipients. Furthermore, the initiation of the SPLT program, donor allocation, surgical aspects, recipient outcomes, and obstacles to developing this procedure will be thoroughly discussed. This information might help provide an optimal strategy for implementing SPLT for 2 adult recipients among current transplantation societies. Meanwhile, potential obstacles to SPLT might be overcome in the near future with growing knowledge, experience, and refinement of surgical techniques. Ultimately, the widespread diffusion of SPLT may increase graft availability and mitigate organ donation shortages. However, SPLT, which divides a deceased donor liver into 2 full hemi-liver grafts for 2 adult recipients, has not achieved consensus among the transplantation community because of variable results.–6 Accordingly, SPLT for 2 adult recipients has not yet gained acceptance as a common practice.Liver transplantation (LT) is common solid organ transplantation that is routinely performed in many transplantation centers worldwide. However, the available liver grafts fail to fulfill the needs of the number of patients requiring LT. Advances in surgical techniques and medical facilities have evolved to maximize liver grafts for transplantation, including living donor LT (LDLT), blood type-incompatible LT, donor from circulation death LT, and deceased donor split LT (SPLT).–12 Therefore, this review summarizes the current status of SPLT, focusing on transplantation for adult recipients. Specifically, the process of SPLT, including the initiation of the transplantation program, donor-recipient matching, surgical aspects, outcomes, and obstacles to be solved for developing this procedure will be thoroughly discussed. This information might help provide an optimal paradigm for the implementation of SPLT for 2 adult recipients under the current allocation system of the transplantation society.As such, SPLT of 2 full hemi-liver grafts for 2 adult recipients remains technically more challenging during organ procurement than other types of deceased donor LT. Meanwhile, potential complications could also be a drawback of utilizing SPLT for 2 adult recipients.2Transection of the hepatic parenchyma has evolved over the last several decades and has contributed dramatically to the safety and effectiveness of liver resection. Specifically, the introduction of ultrasonic cavitation devices using low-frequency ultrasound energy to dissect or fragment hepatic tissues was undoubtedly a transition to a new era of safe liver resection. This surgical device has the advantages of less blood loss and improved visibility of intrahepatic vascular pedicles, and has increased the success rate and safety of liver resection. Subsequently, Pichlmayr et al reported the first SPLT implanting a smaller left lateral graft into a child and a larger right graft into adults in 1988. Soon after, Bismuth et al described the possibility of dividing a deceased donor liver into 2 full hemi-liver grafts for 2 adult recipients. Although both recipients died after SPLT, this attempt opened a new window for LT. Meanwhile, Strong et al reported another milestone in 1990 with LT using a portion of the liver from a living donor. Moreover, LDLT further evolved from using the left lateral graft for children to use a right lobe graft in an adult recipient. As a result of these great advances in the field of LDLT, it has now become a common and routine operation in many major LT centers worldwide.Based on the confidence gained from the experience of liver resection, reduced-size LT in children using a partial liver graft from a deceased donor was first attempted by Bismuth and Houssin in 1984. Of these, only less than 10% were SPLT for 2 adult recipients. As such, LT volume might be an important factor attributed to the infrequent utilization of SPLT. Therefore, the prerequisite for the initiation of the SPLT program might be fulfilled by an adequate volume and experience in liver resection and LT. Moreover, a better understanding and experience in LDLT for adults might be pivotal for the implementation of SPLT for 2 adult recipients. In addition, the improvement of allocation policies for better patient and donor selection, technical refinements, and encouraging widespread diffusion of the surgical technique are all factors related to the success of SPLT.However, SPLT for 2 adults has been developed from the stepwise progression of liver resection, LT, and LDLT. With this approach, a whole deceased donor liver is divided into 2 functioning hemi-liver allografts. Although this might increase the number of donor organs, it remains highly challenging in terms of surgical techniques. Based on an analysis from the United Network for Organ Sharing of the United States, nearly half of the SPLTs were concentrated in 10 transplantation centers that performed ≥20 SPLTs during the study period.33.1,17–20In general, careful donor selection is essential for successful SPLT. However, there is currently no formal algorithm for decision-making while splitting liver grafts from deceased donors. The vital conditions of the donor and graft quality are both important for determining whether the liver graft is suitable for splitting, and splitting for 2 full hemi-liver grafts should be more rigorous than splitting a smaller graft for pediatric recipients. Based on the reviewed data, there are few general principles related to donor criteria proposed for the consideration of split liver grafts for LT Table . Briefly,22 Nonetheless, the utilization of computed tomography to measure the liver volume and anatomical variations of deceased donors might be helpful, but risks to donors during the examination and ethical issues should also be considered.Additionally, Doppler sonography of the liver prior to organ recovery might be helpful in identifying hepatic steatosis and vascular distribution of the liver graft. Specifically, the expected liver volume of hemi-liver grafts can be estimated by calculating the standard liver volume and using the equation utilizing the maximum diameter of the portal vein as described by Lee et al3.2,20,23–26 Nonetheless, the timeframe of hepatic transection should be cautiously considered and minimized as much as possible in both approaches, which could prevent prolonged cold ischemia time in grafts from ex vivo splits and hemodynamic instability in donors during in situ splits. Generally, in situ splits are preferred by transplantation centers with extensive experience in LDLT for hemodynamically stable donors.,20,27,28 Moreover, the cut surface of the hemi-grafts could be sealed with fibrin glue, which might help to reduce bleeding after graft reperfusion.During organ recovery, a thorough inspection of the liver to evaluate the sizes of the right and left lobes, vascular anatomy, and consistency of the hepatic parenchyma by donor surgeons is essential. Cholangiography for the assessment of biliary tract distribution is also mandatory for determining the cut point of the left and right hepatic ducts. Separation of hepatic parenchyma could be performed ex vivo and in situ depending on the hemodynamic stability of donors or as per the surgeon's preference, as previously described.However, the most important challenge facing liver graft splitting is the determination of major vessels and bile duct sharing, an aspect that still suffers from a lack of consensus. Despite this, the principal concept is to divide the major vessels and the bile duct at an optimal point, making it easy to reconstruct vascular inflow and outflow as well as bile duct drainage for graft implantation. Thus, it can prevent the risk of surgical complications from multiple complex anastomoses.–33 With growing experience in LT as well as LDLT, the implementation of microscopic reconstruction for small hepatic arteries and bile ducts may also be accomplished without much difficulty in SPLT using hemi-liver grafts from deceased donors.–36The most common form of sharing vascular and biliary structure for splitting liver graft is illustrated in Figure 3.3 Additionally, the splitting of livers has also been attempted in this context. However, the majority of reports were preclinical or animal models, in which split liver grafts were not transplanted.–42 More recently, ex vivo liver splitting during dynamic machine perfusion has been well described, in which a left lateral liver graft and an extended right liver graft were successfully transplanted into 2 recipients.,44 Importantly, experience from these early attempts perhaps could encourage and facilitate the use of machine perfusion for split full hemi-liver grafts for adult recipients in this way. Nonetheless, more studies are warranted to evaluate the potential clinical benefits of machine perfusion in SPLT and to bring this strategy to clinical application in the future.Machine perfusion has emerged as a novel technique for extending the utilization of marginal liver grafts from non-heart-beating donors.44.1Currently, the whole transplantation society fully respects the priority indications for LT based on the algorithm from the United Network for Organ Sharing (UNOS), the model for end-stage liver disease (MELD) score, and the time on the waiting list. Accordingly, donors eligible for split liver grafts should also rely on recipient matching from the waiting list. Under this algorithm of allocation, liver grafts are usually directed to the sickest recipients with UNOS status I or the highest MELD score.,20,45,46 A potential liver graft should be transplanted as a whole liver if an optimal GRWR cannot be offered to the first-priority recipient. Second, decreased survival has been observed with split liver grafts in high-risk recipients,47,48; thus, surgeons might be reluctant to use split hemi-liver grafts in patients with a high MELD score. Indeed, the sicker recipient might theoretically need a greater liver mass to compensate for the illness during the postoperative recovery period. Nonetheless, numerous reports have shown that the results of SPLT for adult recipients, even at higher MELD scores , were more than acceptable and comparable to those of whole LT.,49–51 Therefore, SPLT for adult recipients with high-MELD scores is justified and could be broadly applied to this candidate population.However, a number of concerns must be taken into consideration when splitting liver grafts for transplantation. First, size matching in terms of graft-to-recipient weight ratio (GRWR) is of utmost importance for partial liver graft LT. Although a minimum GRWR of 0.6% could be acceptable for LDLT, an estimated GRWR of at least 0.8% is recommended for split liver grafts from deceased donors for adult recipients. In such circumstances, the initial intent to expand the donor pool for LT no longer exists. Therefore, the collaboration between different centers with adequate experience in LT and/or SPLT is essential for successfully sharing hemi-liver grafts. Currently, there is no formal allocation system for sharing hemi-liver grafts from SPLT in the transplantation community.,18,29 The secondary hemi-liver graft is usually allocated to a size-matched recipient on the wait-list of the same transplantation centers.Moreover, leftover hemi-liver graft sharing is another significant issue for the utilization of SPLT in adult recipients. The fear that a good-quality graft divided into 2 marginal hemi-liver grafts might endanger the recipients has withdrawn most transplantation centers from using the leftover hemi-liver grafts obtained from SPLT for adult recipients. Based on an analysis of the UNOS registration data, 16% of the secondary split grafts were discarded for various reasons. All adult recipients on the waiting list for LT could be selected at any time of organ allocation for SPLT based on the blood-type compatibility and donor-recipient size match. The Split-Liver Network program can make real-time matches between the potential donor and registered patients according to size-based matched donor/patients, and determine hemi-liver graft allocation once the donor is considered eligible for the split liver procedure. All transplantation centers in this program could share hemi-liver grafts for SPLT. Accordingly, widely encouraging SPLT might be able to mitigate the current severe organ shortage and reduce wait-list mortality.However, the Split-Liver Group of the North Italy Transplantation program has developed a promising SPLT policy for 2 adult recipients.4.2,52–54 Whereas numerous other reports demonstrated that SPLT, LDLT, and whole LT had comparable outcomes.–20,55–59 However, one would expect that outcomes of SPLT for adult recipients might have progressively improved over time owing to the growing knowledge and experience with LT.The majority of results gained from SPLT for 2 adult recipients remain variable and have only been reported by a few experienced centers. Table ,18,60–63 Of these factors, preoperative estimation of graft weight for recipient matching could be the most unpredictable factor, as it is usually a major concern affecting outcomes in adult SPLT. Although many equations were used to calculate liver volume, none of them were able to estimate the true liver volume and graft weight. Therefore, hemi-liver graft recovery from a deceased donor may be inadequate for matched adult recipients, leading to small-for-size grafts as well as graft failure.In addition, factors affecting patient and graft survival rates were not definite as well. Numerous risk factors have been observed for poor outcomes of SPLT for adult recipients and critically ill recipients, with a sufficient volume or weight of the hemi-liver grafts, high-risk donors, long ischemia time (>10 hours), steatosis grafts, retransplantation patients, and low-volume LT centers were the most mentioned prognostic factors.5,65 However, splitting the liver graft can undoubtedly increase graft availability and potentially increase the number of adult transplant recipients. Although few reports have reported unsatisfactory results, SPLT should not be discouraged because of the considerably high incidence of patient mortality in the wait-list.Organ shortage is the most important hindrance to organ transplantation worldwide. Although LDLT is increasingly performed to overcome the shortage of liver donations for transplantation, splitting the liver into 2 hemi-liver grafts could be another promising strategy to maximize organ donation from a deceased donor and increase the donor pool for LT. The answer to whether 1 plus 1 equals 2, in terms of SPLT, might be obvious and sadly “no.” The SPLT network program can be established under the National Liver Transplantation Organization. Accordingly, transplantation centers with adequate experience in SPLT or willing to develop SPLT could join the program. Subsequently, these transplantation centers could closely cooperate in terms of organ sharing and surgical techniques, under the surveillance of the SPLT program.Moreover, improving allocation and organ sharing policies by the transplantation society might help encourage the widespread diffusion of SPLT for adult recipients. The split-liver network program, as proposed by the North Italy Transplant Organization, is a promising strategy for the implementation of SPLT.Additionally, informed consent on the willingness to accept a split hemi-liver graft should be signed by patients when they are registered on the waiting list. All potential donors who meet the criteria for split-liver grafts should be included in the SPLT program for organ sharing. The SPLT program can make real-time matches of hemi-liver grafts with recipients who had signed the informed consent of SPLT, and on the basis of prioritization of national organ sharing with size-matched graft/recipients. Importantly, trust and collaboration between different centers are fundamental for successfully sharing hemi-liver grafts under this program as well.6As a result of improvements in surgical techniques and perioperative patient care, LT has now become a common and routine operation in many transplantation centers worldwide. Although the surgical technique may be a crucial factor for the success of LT, proper donor and recipient selection is of the utmost importance for the success of SPLT and affects long-term graft and patient survival. Meanwhile, more widespread use of SPLT for 2 adults would also improve outcomes by growing experience and refinement of surgical techniques. Furthermore, there is an urgent need to establish a formal organ-sharing program in terms of SPLT for pediatric, adult, or adult recipients under current organ transplantation organizations. Ultimately, the widespread diffusion of SPLT in the transplantation community may increase graft availability, benefit patients awaiting LT, and mitigate the high incidence of wait-list mortality in the setting of extreme organ shortage.This work was supported by grants from the Chang Gung Medical Research Program (CMRPG3K1461) to K.-M. Chan. In addition, the authors wish to thank Miss Ingrid Kuo and the Center for Big Data Analytics and Statistics (Grant no. CLRPG3D0048) at Chang Gung Memorial Hospital for creating the illustrations used herein.Acquisition of data: Kun-Ming Chan, Hao-Chien Hung, Jin-Chiao Lee, Tsung-Han Wu, Chih-Hsien Cheng, Chen-Fang Lee, Ting-Jung Wu, Hong-Shiue Chou, Wei-Chen Lee.Conceptualization: Kun-Ming Chan, Wei-Chen Lee.Critical revision of the manuscript for important intellectual content: Kun-Ming Chan, Wei-Chen Lee.Data curation: Kun-Ming Chan, Hao-Chien Hung, Jin-Chiao Lee, Tsung-Han Wu, Yu-Chao Wang, Chih-Hsien Cheng, Chen-Fang Lee, Ting-Jung Wu, Hong-Shiue Chou.Investigation: Kun-Ming Chan.Manuscript drafting: Kun-Ming Chan.Supervision: Wei-Chen Lee.Validation: Kun-Ming Chan.Writing – original draft: Kun-Ming Chan.


Iron oxide nanoparticles (IONPs) possess versatile utility in cancer theranostics, thus, they have drawn enormous interest in the cancer research field. Herein, we prepared polyethylene glycol (PEG)-conjugated and starch-coated IONPs (“PEG–starch–IONPs”), and assessed their applicability for photothermal treatment (PTT) of cancer. The prepared PEG–starch–IONPs were investigated for their physical properties by transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, and dynamic light scattering (DLS). The pharmacokinetic study results showed a significant extension in the plasma half-life by PEGylation, which led to a markedly increased (5.7-fold) tumor accumulation. When PEG–starch–IONPs were evaluated for their photothermal activity, notably, they displayed marked and reproducible heating effects selectively on the tumor site with laser irradiation. Lastly, efficacy studies demonstrated that PEG–starch–IONPs-based PTT may be a promising mode of cancer therapy. Photothermal therapy (PTT) is a local treatment modality that relies on the activation of light-absorbing agents by electromagnetic radiation, such as pulsed laser irradiation at the near-infrared (NIR) wavelength . Upon la® in USA), with a size of 120 to 180 nm, coated with dextran, and ferucarbotran (Resovist®), with a size of about 60 nm, coated with carboxydextran [Iron oxide nanoparticles (IONPs), clinically available MRI contrast agents, have drawn great interest in the pharmaceutical research fields ,10. For ydextran . As impoydextran .Proper application of surface-coating materials can stabilize IONPs, avoid agglomeration, and reduce toxicity issues . The coaApart from the low toxicity, the IONPs possess a unique property, which is magnetic susceptibility ,19. By fFor effective, but safe, cancer PTT with the IONPs, there remain critical challenges to overcome. One of the challenges would be how to irradiate laser selectively to the tumor tissue, while the other is to accomplish high, but selective, tumor accumulation of the IONPs . SpecifiIn this research, we applied the stable chemical conjugation procedure to prepare polyethylene glycol (PEG)-conjugated and starch-coated IONPs (PEG–starch–IONPs), and fully characterized the physicochemical and photothermal properties. Furthermore, their applicability for PTT was evaluated in vitro and in vivo. The study results suggested that PEG–starch–IONPs could serve as an effective PTT agent for the treatment of cancer.Starch-coated IONPs (“Starch-IONPs”) was purchased from Chemicell GmbH . Ammonium hydroxide and epichlorohydrin were purchased from Sigma-Aldrich . Methoxy PEG Succinimidyl Carboxymethyl Ester  was obtained from JenKem Technology USA .The preparation of PEG–starch–IONPs was performed by the procedures of Zhang et al. . BrieflyThe iron (Fe) contents of PEG–starch–IONPs were analyzed by inductively coupled plasma optical emission spectroscopy (ICP-OES) using an Optima 5300DV spectrometer . The amine and PEG contents were quantified using ninhydrin assay  and bari2, MDL-III-885; Changchun New Industries Optoelectronics Tech Co. Ltd., Changchun, China) and the temperature rise was monitored using an IR camera . The assay was performed with (1) varying starch–IONP and PEG–starch–IONP concentrations (0–200 μg Fe/mL) at fixed laser power (1.3 W), and (2) different laser powers (0.8–1.3 W) at a given PEG–starch–IONP concentration (200 μg Fe/mL). In addition, to assess the photothermal stability, the PEG–starch–IONP suspension (100 μgFe/mL) was irradiated with a laser by a switch “on and off” mode at 1 W.To evaluate the photothermal activity, the starch–IONP and PEG–starch–IONP suspensions were irradiated with a laser  were seeded onto 96-well plates and incubated o.n. The next day, the cells were treated with either PBS or PEG–starch–IONPs (at 100 μg Fe/mL), and then the laser was irradiated to the cells for 10 min at different laser powers . After incubation for 48 h, the cells were washed with PBS, and then the relative cell viability was determined by WST-1 assay .The U87 MG human glioblastoma cell line was a kind gift from Prof. Sun Young Han . The cell culture was maintained in 10% FBS containing DMEM medium (with 1% antibiotic antimycotic and 1% penicillin–streptomycin) and kept in a cell incubator at 37 °C. To assess the photothermal cytotoxic effects of PEG–starch–IONPs, the U87 MG cells .i.v.) administered with either starch–IONPs or PEG–starch–IONPs (12 mg Fe/kg) (N = 3). After then, blood samples were collected at pre-determined time points . The plasma was instantly separated from the blood by centrifugation (3000 rpm for 3 min) and the Fe contents of the samples were measured by ICP-OES.The PK profiles of PEG–starch–IONPs were determined using ICR mice . After acclimation of the mice in the animal facility for a week, the mice were intravenously (7 cells per mouse) were implanted in the right-side thigh of athymic nude mice . When the average tumor size reached 200 mm3, the mice were administered with either starch–IONPs or PEG–starch–IONPs by i.v. injection (24 mg Fe/kg). At 4 h post-administration, the mice were anesthetized (with i.p. injection of ketamine/xylazine), and then a laser was irradiated to the tumor region for 10 min at varying laser powers (0.6–1.0 W) (N = 3). The temperature of the tumor region was measured with an IR camera .U87 MG cells : (1) PBS control, (2) starch–IONPs, and (3) PEG–starch–IONPs and administered with the samples (24 mg Fe/kg) by i.v. injection. At 4 h post-administration, the mice were euthanized, and the tumors were harvested. The tumors were then digested by incubation in concentrated hydrochloric acid (HCl) and the Fe contents of the particles were quantified by ICP-OES.When the average tumor size reached 200 mm3 (day 1), the U87 MG s.c. xenograft tumor-bearing nude mice were divided into the following 4 groups (N = 5): (1) PBS control, (2) starch–IONPs + PTT (starch–IONPs: 24 mg Fe/kg), (3) PEG–starch–IONPs (24 mg Fe/kg), and (4) PEG–starch–IONPs + PTT (PEG–starch–IONPs: 24 mg Fe/kg). For groups 2 and 4, at 4 h post-administration, a laser was irradiated for 10 min at the tumor region (at a power of 0.9 W) after anesthetizing the mice with ketamine/xylazine. The size of the tumors was monitored daily using a vernier caliper. The tumor size was calculated with the formula V (mm3) = (a2 × b)/2. V is tumor volume, a is tumor width, and b is tumor length. The study was terminated when the average tumor volume of the control mice reached 1000 mm3.When the average tumor size reached 100 mmt-test or 1-way ANOVA (Tukey’s multiple comparison test as the post hoc test) in GraphPad Prism 5.03 .Data are presented as average ± standard error of the mean (SEM). A statistically significant difference among the groups was determined using either Student’s 3O4 core structures , and the amine and PEG contents . Based o−1, (2) the C–O–C stretching band at 1070 cm−1, and (3) the vibration frequencies at modes of C–C–H, O–C–H, and C–O–H angles at around 1330 cm−1. Finally, the hydroxyl groups of PEG provided a broad and intense peak in the range of 3000 to 3500 cm−1. In the FT-IR spectrum of PEG–starch–IONPs, vibration frequencies within the iron oxide cores compatible with Fe–O and FeO–H bonds were detected at 542 and 3400 cm−1, respectively. The spectrum of PEG did not show the absorption from iron between 500 and 600 cm−1. In comparison with starch–IONPs, the representative peak at 1070 cm−1 that attributes to the “C-O-C” stretching vibration was observed from both the IR spectra of PEG and PEG–starch–IONPs, suggesting the presence of PEG moieties on the surface of PEG–starch–IONPs. For pure PEG or PEG–starch–IONPs, C–H bending vibrations from the carbon chain were detected in the range of 1200 to 1500 cm−1. Lastly, the size stability of PEG–starch–IONPs in plasma was characterized in vitro. As shown in The successful PEGylation of starch–IONPs was further verified by FT-IR analysis . As showPhoto-sensitive metal nanomaterials, such as IONPs, can absorb NIR light and generate heat . By explThe photothermal cytotoxic effects of PEG–starch–IONPs were assessed on U87 MG cells. The results are shown in ® in pharmacokinetic studies using rats showed a blood half-life of 1.35 h [The PK profiles of PEG–starch–IONPs were determined in ICR mice. The plasma concentration-versus-time profiles of starch–IONPs and PEG–starch–IONPs are shown in f 1.35 h , and othf 1.35 h ,29. PEGyf 1.35 h ,49.s.c. tumor-bearing nude mice. When the tumor size reached 200 mm3, the PEG–starch–IONP suspension (24 mg Fe/kg) was administered by i.v. injection and, at 4 h post-administration, a laser was irradiated to the tumor site. The representative IR camera images of the mice irradiated with laser after treatment of PBS, starch–IONPs and PEG–starch–IONPs, are shown in ® or Resovist®, coated with dextran [The photothermal activity of PEG–starch–IONPs was evaluated in U87 MG  dextran . Apparens.c. xenograft tumor-bearing mice. Adopting the optimal experimental conditions (24 mg Fe/kg of PEG–starch–IONPs administration by tail vein injection and laser irradiation at 4 h post-administration at 0.9 W laser power) identified from the in vivo photothermal activity assay, the efficacy studies were carried out with a total of four groups. The tumor growth profiles are displayed in 3 for the PBS control, starch–IONPs + PTT, PEG–starch–IONPs, and PEG–starch–IONPs + PTT, respectively. Notably, the study results demonstrated that a single PTT treatment with PEG–starch–IONPs was sufficient to significantly inhibit tumor growth. Yu et al. reported the therapeutic effects in neuroblastoma by photothermal activity of IONPs modified with mPEG-b-PHEP copolymers, and compared the photothermal therapy by IONP constructs with the combined therapy  [The feasibility of PEG–starch–IONPs-based PTT was evaluated in U87 MG therapy) . A singlIn this research, PEG–starch–IONPs were synthesized and their applicability as a PTT agent was characterized in vitro and in vivo. Notably, through the in vitro assays, PEG–starch–IONPs showed stable and reproducible photothermal effects at repetitive laser irradiation. More importantly, above 0.9 W of laser power, the tumor temperature could be raised to higher than 45 °C necessary for photothermal ablation of the tumor. Compared to dextran- or starch-coated IONPs in previous reports, PEG–starch–IONPs showed an extended half-life in plasma in vivo. Notably, in this study, 5.7-fold higher tumor accumulation was obtained with PEG–starch–IONPs compared to starch–IONPs, finally producing efficient photothermal effects by PEG–starch–IONPs. Based on our results, in vivo tumor ablation could be achieved by administering 24 mg Fe/kg of PEG–starch–IONPs, and applying 0.9 W laser power at the NIR wavelength of 885 nm at 4 h post-administration. Conclusively, the preliminary efficacy study results confirmed that a single PTT with PEG–starch–IONPs was sufficient for effective inhibition of tumor growth.


Pre-operative identification of patients with inadequate hamstring graft for anterior cruciate ligament reconstruction is still a subject of interest. The purpose of this study is to correlate dimension of a harvested dimensions graft with patient physical anthropometric variables.This cohort study included 280 patients  scheduled for primary anterior cruciate ligament (ACL) reconstruction. Interrelationships between quadruple semitendinosus (ST) graft and anthropometric parameters  were assessed using Pearson Correlation test and regression analysis. Difference among gender was analysed using Mann Whitney and t test. The observed graft diameter was also compared with the literature using Bland – Altman plot.Mean age of cohort was 29 years , mean height was 1.69m , mean weight was 75 kg  and mean BMI was 26kg/m2 (range 16.65-40.40kg/m2). Mean quadruple length of harvested ST graft was 7cm  and mean diameter was 8mm . Only height and weight were significantly correlated with graft length and diameter in both sex . Female, compared to male, had significantly smaller (p<0.0001) and thinner graft (p<0.0001). There was a strong agreement between the literature and our observed graft diameter, but with an overestimated graft diameter in 18.5% of the cases.Among anthropometric parameter, only height and weight had moderate positive correlation with graft diameter. Males had longer and wider ST graft in contrast to age-matched female group. Among all, hamstring graft became widely popular because of its comparable biomechanical properties, fewer donor site complications and better outcome on midterm basis3. Also, newer fixation techniques like endobuttons and tight ropes reassure better outcome with hamstring graft4. Unlike BPTB, hamstring tendon length and diameter cannot be controlled and are neither consistent during harvest. Hence, whether the hamstring graft is of sufficient dimension in a particular patient becomes questionable. Diameter of minimum 8mm is recommended to avoid high risk of rupture for hamstring graft6. Furthermore, beforehand prediction of hamstring graft dimension becomes very useful in population where allografts are not available, thus switching over to other graft options must be considered if insufficient graft is anticipated. Previously, studies have been conducted to correlate patient anthropometric data to predict graft dimensions15. Some authors even suggested equations to predict graft dimension based upon patient anthropometric data, but there is poor consensus13. The quadruple-strand semitendinosus hamstring graft is expanding its acceptance by means of better biomechanical strength in contrast to double-strand gracilis or semitendinosus grafts16. Authors also reported better result when ACL reconstruction is done using semitendinosus (ST) graft alone compared to ST and gracillis together (STG). Internal rotation torque deficit is significantly higher in STG group compared to ST group17. Also, external to internal rotation ratio was significantly higher in STG group in contrast to ST group17. In our centre, we consider only ST graft for single bundle ACL reconstruction unless graft diameter falls below <7mm or of inadequate length. There is an insufficiency of literature that has desired to anticipate quadrupled graft dimensions from single-strand tendon.Ligament reconstruction in Anterior cruciate ligament (ACL) deficient knee is a well recommended treatment. Multiple graft options like bone patellar tendon bone graft (BPTB), hamstring graft, distal iliotibial tract can be selected for ACL reconstruction depending upon surgeon preference and tissues availabilityOur primary motive in this cohort study is to analyse large Indian population anthropometric data like age, height, weight, and body mass index (BMI) and to predict semitendinosus graft dimension. We assume that the length and diameter of semitendinosus can be predicted from patient anthropometric data. We also hypothesise that the graft dimensions are independent of gender in age matched group.This cohort study was conducted from June 2014 to June 2018, in the Department of Orthopaedics at Sir Ganga Ram Hospital, New Delhi, after ethical committee and departmental review board approval. Sample size was estimated to keep type 1  error at 0.05 and beta error (β) at 0.01 to attain 90% power of study. A total of 395 skeletally mature adults  were admitted during study time for arthroscopic ACL reconstruction. A total of 115 patients were excluded as these were revision surgeries in which hamstring graft had already been taken from ipsilateral side. Also, patient with long standing diabetes mellitus (HbA1c ≥9), connective tissue disorders and neuromuscular disorders were excluded from study. Finally, 280 patients  with mean age of 29 years who underwent primary ACL reconstruction in our institution using semitendinosus autograft were reviewed.Anthropometric variables age, sex, height, weight, and body mass index (BMI) were documented day before surgery. Anthropometric data was collected by two senior registrar level persons. Measurements were taken by standard standiometer and digital weighing machine. BMI was calculated from height and weight using standard formula. All graft harvest procedure was performed by the single senior surgeon with standard 4cm long incision over anteromedial tibia approximately 4cm distal to the joint line and 3cm medial to the tibial tuberosity in 90° knee flexion. The pes-anserinus was exposed and semitendinosus mobilised proximally, detached, and transfixed by Ethibond no. 5 suture. Ends of the suture were passed through the conical end of the tendon stripper. All sides of the tendon were palpated to make sure there are no fibrous extensions. With the knee in 90° flexion, the surgeon passed the tendon stripper and tendon was released proximally by controlled tension on the tendon while advancing the stripper proximally.After procuring semitendinosis, all the loose muscle tags were freed off the tendon and its proximal end transfixed in a similar fashion as the distal end. The final harvested length and diameter of the semitendinosus graft with periosteum was measured after making the graft quadrupled with a sterile ruler and graft sizer. The end-to-end length of four stranded tendon graft was considered as graft length (GL). Slotted cylinders with 0.5mm increments was utilised to record graft diameter (GD). The lowest diameter that permitted easy passage of the four standard graft was considered as final diameter. Semitendinosus grafts length and diameter were co-related with physical variables and a model was made for prediction of hamstring graft length and diameter.Data was summarised as mean and standard deviation. Pearson correlation coefficient and multiple linear regression models were used to valuate strength of relationship between graft dimensions and predictor variables i.e., height, weight, BMI, age, and gender. Also, we anticipated graft diameter using formula in literature and compared it with observed graft diameter using Bland-Altman plot. Because of the discrepancies in male and female sample sizes, graft dimensions were compared using non-parametric Mann Whitney test and T test. Two tailed p value was used for statistical significance of correlation. P value <.05 was considered for the level of significance, for all analysis (SPSS version 22).This cohort study included 280 mature adults  with mean age of 29 years , mean height of 1.7m , mean weight of 75kg  and mean BMI of 26kg/m2 (range 16.65-40.40kg/m2) .Mean quadruple length of harvested graft was 7cm  and mean diameter was 8mm . On balancing between normally distributed age-matched male and female groups, quadruple graft length (GL) was significantly lower in the female group. After applying t test, t value was 5.58  and on Mann Whitney test, z score was 4.98  .Similarly for quadruple graft diameter (GD), after applying t test  and Mann Whitney test , the male group had significantly higher value compared to female group in age-matched equal distribution .On assessing the interrelationship between graft dimension and anthropometric data, coefficient affirmed statistically significant positive correlation in graft dimensions (GL and GD) and patient height and weight , III. FoGL = Height (in meter) × 4.162 + weight (in kg) × 0.003 – 0.194GD = Height (in meter) × 4.995 + weight (in kg) × 0.015 - 1.369et al8 equation for predicting GD i.e. graft diameter = height (cm) ×0.03+2.4, and anticipated the graft diameter in our patient. The anticipated diameter was compared to observed graft diameter during surgery and a Bland- Altman plot was plotted . The anticipated value of graft diameter, if more than half (0.25) of 0.5mm, was corrected to next largest diameter.From linear regression equation, we calculated that patients with height less than 164cm and weight less than 66kg were at risk for GD less than 8mm.We made use of Tuman  plotted , Fig. 4 18. Magnussen et al retrospectively analysed 256 patients with comparable male to female ratio (1.13:1) and concluded a high revision rate with graft diameter (ST-G) of ≤8mm5. Revision rate in graft diameter 7.5mm/8mm was 6.5% and in size ≤7mm was 13.6%. With graft diameter >8mm, the revision rate was 1.7%. Similarly, Park et al in their analysis found high revision rate in graft diameter <8mm (5.2%) compared to graft diameter ≥8mm (0%)18. The author concluded that the revision rate did not depend upon patient characteristics but only on graft diameter. Also, Mariscalco et al in their multicentric cohort study noticed a higher revision rate with graft diameter ≤8mm (7%) compared to >8mm (0%) with two-year follow-up6.Quadruple hamstring graft is frequently used for ACL reconstruction. Graft diameter is theorised to be an important parameter to predict long term outcome9. We tried to validate the equation by Tuman et al and found a firm compliance with the equation8. Tuman et al also noticed height as only significant predictor of graft size8. They observed the shorter the height, the shorter the diameter and they did not observe the same interrelationship with other factors like BMI, weight, age or gender. They found that a height <147cm would likely to have a graft diameter <7mm. Treme et al observed among all data, weight was best predictor of graft diameter9. They observed height had a low magnitude of prediction for diameter but was the best predictor for graft length along with leg length for ST. Their analysis further indicated that weight <50kg and height <140cm were at highest risk of graft diameter <7mm. In gender specific analysis for graft diameter, they found age, BMI and ipsilateral thigh circumference as best predictors in men while in female, only thigh circumference was the chief predictor. For graft length, they concluded that for female, height and thigh length were important predictors and in male, no such correlation was found.In literature, there are a fair number of studies showing interrelationship between patient anthropometry and graft dimension. Only few studies had concluded a strong correlation between patient variable and graft dimension after multiple stepwise regression analysis. Additionally, in the literature, height was most consistently correlated with graft size and authors had also suggested height as the only variable used in the equation to anticipate graft diameteret al in their research project, observed that the patient variable like height, weight, thigh circumference and leg length were in significant positive correlation with ST and gracills diameter13. However, after further analysis, they concluded that the ST diameter was strongly dependent upon leg length and gracillis was dependent on height. Goyal et al concluded that height and thigh length could be relayed upon to predict graft dimension, but they lacked strong association7. After multiple regression analysis they noticed only height was significantly associated with graft dimension in their study population. They mentioned height of less than 147cm as being at risk of graft diameter <7mm.Gupta et al and Pinheiro et al in their analysis agreed for height but not weight as a strong predictor of graft diameter for both male and female groups15. However, they had not come up with any threshold height for scarce graft. The mean age our cohort was 29 years, with a range of 17-50 years. On correlation and regression analysis, we did not find any significant association between age and graft dimension. Our finding was in keeping with those of Treme et al, Schwartzberg et al, and Biosvert et al and Ma et al, which also concluded that graft dimensions were independent of age14.We had found height and weight were moderately associated with graft dimensions in both male and female. Graft length and diameter was significantly more in the male group compare to age-matched female group. From our study we concluded that patient height of 164cm and weight 66kg were at risk for graft diameter of ≤8mm. For graft diameter ≤7mm, height of 148cm was the risk factor, which was in accordance with the literature. Also, Ma et al analysed 50 patients and suggested that BMI <18kg/m2 as being at risk for graft diameter <7mm. In our cohort, we had three patients with BMI <18 kg/m2, and all had diameter >7mm9. Biosvert et al concluded that low BMI was not a predictor for graft size but high BMI might predict graft size in men11. Our finding did not suggest that BMI has a role in predicting graft dimension in male as well in female.Mean BMI in our cohort was 26kg/m2  in both male and female groups. On analysis, there was a weak positive correlation between BMI and graft diameter and graft length in both gender groups but it was statistically insignificant. Treme The main limitation of our study was small female sample size. Because of the disproportionate sample size for the two genders, drawing exact conclusion for both sample groups was difficult. Secondly, only ST graft dimensions were recorded. Though we only considered the ST graft of our single bundle ACL reconstruction, we still consider it as our limitation. Thirdly, we had not taken other patient parameters like thigh length, leg length and thigh circumference into consideration. But they could be in correlation with graft dimension. Additionally, we had not validated our equation to determine graft diameter pre-operatively. Further research is necessary to approve our equation.Our study revealed that height and weight were moderately correlated with graft diameter and graft length in both genders. Graft dimensions were independent of age and gender in adult age group. However, the male group had statistically significant larger diameter and length of ST graft compared to age-matched female group.


This commentary describes the growth of small-angle scattering as a technique for structural characterization in noncrystalline systems across chemistry, biology and materials and how the international community continues to grow and prosper through highly successful international meetings and a strategic collaborative relationship with the International Union of Crystallography. Journal of Applied Crystallography. Since the early 2000s, the relationship between the international SAS community represented at the triennial SAS meetings and the IUCr has been strengthened and deepened through formal cooperation and collaboration in a number of mutually beneficial activities that have supported the growth and health of the field and the IUCr.Small-angle scattering emerged as a tool for studying noncrystalline structures from early observations around 1930 that there was a relationship between the extent of the scattering and the size of the scattering object. André Guinier, a leading figure in the development of the field, noted in his summary findings from the first Conference on Small Angle Scattering in 1958 that the technique would be of value to study ‘submicroscopical inhomogeneities’ and further provided a means of ‘observation [that had] in the past restricted the field of application of the X-ray method.’ In 1965 the first of what became a highly successful series of Small-Angle Scattering (SAS) meetings held approximately every three years took place in Syracuse, NY, USA, and many of these ongoing meetings published their proceedings and highlights in the International Union of Crystallography (IUCr)  Final summary remarks were contributed by André Guinier , and the proceedings were published in the In many ways, the 1958 conference could be considered the zeroth meeting for what would become the very successful series of meetings that would bring together the international SAS community across all fields to advance and grow SAS applications. It was just seven years on, in 1965, that what is regarded as the first of this series was held in Syracuse, New York, USA. Since then, the international SAS community has come together to meet approximately every three years . Even so, there was a strong IUCr connection that recognized SAS as a field of crystallography, with the publication of conference proceedings for many of the meetings in Journal of Applied Crystallography  saw value in greater collaboration between the IUCr and the triennial SAS meeting organizers. An agreement was negotiated wherein the international SAS community would adopt IUCr standards for speaker diversity and venue selection for the triennial SAS conference and the meeting would become an IUCr-sponsored meeting. That sponsorship would include support for students to attend and to enable participation from developing countries, as well as the establishment of the IUCr Guinier Prize of USD 5000, honouring the pioneering work of André Guinier. The Guinier Prize would be awarded for ‘lifetime achievement, a major breakthrough, or an outstanding contribution to the field of small angle scattering.’http://www.cansas.org/) that have grown spontaneously from the SAS conference community.As part of these negotiations, and in response to IUCr concerns to avoid scheduling clashes, the triennial SAS conference was moved out of the Congress years: hence the four-year break between the 2002 conference in Venice, Italy, and the 2006 conference in Kyoto, Japan Table 1. Since t3.e.g. ensuring geographical diversity, programme committee diversity, local organizing capacity, adequate conference facilities, affordable accommodation, accessible food outlets, budgets with cost estimates etc.) are presented to the conference participants for a vote. In this way, the participants in the meeting still choose their future venue, but with the assurance that the proposed hosts are fully prepared for the challenging job they will have and with a full six years to prepare.An important mechanism to strengthen and sustain the IUCr–international SAS community connection has been to include IUCr CSAS members in processes for future conference venue selection and the selection of the Guinier Prize recipients. To this end, a formal process was established for venue selection for future meetings based on proposals submitted at least two meetings prior. The proposals are reviewed by representatives of the current triennial SAS meeting organizing committee members and members of CSAS. Qualified proposals based on a set of criteria agreed by the review committee . This standard was drafted in ISO/TC 24/SC4/WG10 where Technical Committee (TC) 24 is ‘Particle characterization including sieving’, sub-committee (SC) 4 is ‘Particle size characterization’ and Working Group (WG) 10 is ‘Small angle X-ray scattering method’. The same working group is now focused on surface area measurement.The SAS conferences and associated open CSAS meetings were important venues for discussion and dissemination of information by CSAS members who were leading efforts to establish a universal SAXS intensity standard . This growth trajectory was the subject of considerable discussion at a meeting of CSAS in Kyoto at SAS2006, where several participants suggested that standards for the publication of biomolecular SAS data and models were needed. The topic was predictably controversial as there were legitimate concerns that efforts to have standards could have unintended consequences and restrict publication in ways that were not appropriate. With the seeds of this effort having been planted in Kyoto, however, there were many follow up discussions at subsequent triennial SAS meetings and IUCr Congresses. These discussions were expanded with the establishment of a SAS validation task force (SASvtf)   and a special session  for the upcoming 25th Congress . IUCr journals will continue to be a popular choice for leading SAS research, with an array of journals that are natural homes for SAS applications across chemistry, biology and materials, as well as for further technical developments in instrumentation, analysis and standards development. While the era of conventional conference proceedings in IUCr journals is effectively over, special issues of The IUCr pioneered the development of standards, common data formats, open-access data and education in the field of crystallography, diffraction and scattering, and the SAS community represented at the triennial SAS meetings is very active in tackling these issues in their respective subdisciplines. Ongoing cooperation in these activities will be of great benefit, providing for knowledge transfer and collaboration and, importantly, the avoidance of multiple divergent efforts to achieve the same goal.


In clinical practice, it is observed that the hamstring tendon graft, despite being first choice in knee ligament reconstruction, may not present adequate size. Therefore, it becomes necessary to search for other graft alternatives. In this context, the peroneus longus tendon arises as an option to replace or complement other grafts. The surgeon can opt to use the tendon in its totality or only its anterior half, presenting adequate length, diameter, and biomechanics, without major repercussions for the donor site. In this study, we report a case of an athlete in which the autologous hamstring tendon graft did not present the adequate diameter for anterior cruciate ligament reconstruction. It was, then, necessary to use the anterior half of the peroneus longus tendon. Because of the lower frequency of anterior pain and extension restriction complaints, the majority of the Anterior Cruciate Ligament (ACL) reconstructions are performed with the use of the gracilis (G) and semitendinosus (ST) tendon grafts. On the other hand, some of these grafts do not exceed 8.0 mm of diameter, thus presenting higher risk of failure . RecentlIn this case report, we used a combination of G and ST and the anterior half of PL (AHPL) for ACL reconstruction in a soccer athlete that presented a G+ST graft with 7.0 mm of diameter. We obtained patient consent to publish the case and the images. The study was approved by the ethics committee of the institution with the protocol number 34826120.5.0000.5479, and the SCARE criteria were used for its formulation.A 21-year-old male patient  attended our sports trauma ambulatory complaining about left knee pain and instability after rotational trauma during soccer practice. Physical examination showed Lachman, Anterior Drawer, and Pivot Shift test positives for ACL lesion, which was confirmed by magnetic resonance imaging. The patient was submitted to ACL reconstruction.The surgery was performed with the patient in the supine position, under spinal anesthesia and sedation. A pneumatic tourniquet was placed on the left thigh and inflated after limb exsanguination. The procedure was accomplished by the senior surgeon of the team. Standardized anterolateral and anteromedial arthroscopic portals were used. After joint inventory, ACL lesion was confirmed.A longitudinal incision of approximately 3 cm was made, distal to the knee joint, on the pes anserinus site. The fascia of the sartorius muscle and the ST and G tendons were identified. A transverse incision was made in the sartorius fascia. ST and G tendons are repaired with No. 1.0 Vicryl thread , and its proximal insertions are removed with the aid of a tenotome.ST and G tendons were folded to form a single quadruple graft, presenting 7.0 mm of diameter and 11 cm of length . To augmA single longitudinal incision of approximately 3 cm was made in the posterolateral region of the fibula over the PL. The incision started 3 cm proximal to the most distal point of the lateral malleolus . The subThe PL graft was incorporated into the ST+G grafts forming a sixfold graft with 9.0 mm of diameter and 15 cm length .Reconstruction was performed through anatomic positioning to create the femoral and tibial tunnels, and guides were used to make them. Initially, the femoral tunnel is performed (tunnel for button passage followed by graft tunnel) using transportal technique. After that, the tibial tunnel was made. The sixfold graft, positioned on the adjustable loop button , was passed through the tunnels. After loop adjustment and graft positioning check, tibial fixation was made with interference screw .The patient was assessed before and after the procedure for knee pain with Visual Analogic Scale (VAS), and subjective evaluation with International Documentation Committee (IKDC) score and Lysholm Knee Scoring Scale was performed. The patient was also submitted to Foot and Ankle Disability Index Score (FADI) and American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS) to evaluate modifications on the PL donor site.Previously to the surgery, the scores mentioned above were measured. The patient presented 47.1% on IKDC, 47% on Lysholm, 9 on VAS, and 100% on AOFAS and FADI. On physical examination, Lachman Test 3+/4+, Anterior Drawer Test 3+/4+, and Pivot Shift Test 3+/4+ were presented. The patient attended the appointments with no complaints and was submitted to physical rehabilitation. After three months of follow-up, the scores were applied again. The results were as follows: IKDC 63%, Lysholm 95%, VAS 8, and AOFAS and FADI 100% . The patThe hamstring tendons are the first choice of graft for ACL reconstruction and usually have an adequate size. However, in clinical practice, it was observed in some cases that the size of the graft might not be sufficient , making The PL tendon arises thus as a viable choice of graft for knee ligament reconstructions. Zhao and Huangfu published a cadaveric study in 2012, showing that load to rupture of PL is similar to ST and higher than G, proving that it is a good option from the biomechanical point of view, to complement or replace the hamstring graft . There aFor a graft to be considered ideal, it must have enough resistance, be easily and safely harvested, with no functional impairment to the donor site . The AHP


Living beings modulate the impedance of their joints to interact proficiently, robustly, and safely with the environment. These observations inspired the design of soft articulated robots with the development of Variable Impedance and Variable Stiffness Actuators. However, designing them remains a challenging task due to their mechanical complexity, encumbrance, and weight, but also due to the different specifications that the wide range of applications requires. For instance, as prostheses or parts of humanoid systems, there is currently a need for multi-degree-of-freedom joints that have abilities similar to those of human articulations. Toward this goal, we propose a new compact and configurable design for a two-degree-of-freedom variable stiffness joint that can match the passive behavior of a human wrist and ankle. Using only three motors, this joint can control its equilibrium orientation around two perpendicular axes and its overall stiffness as a one-dimensional parameter, like the co-contraction of human muscles. The kinematic architecture builds upon a state-of-the-art rigid parallel mechanism with the addition of nonlinear elastic elements to allow the control of the stiffness. The mechanical parameters of the proposed system can be optimized to match desired passive compliant behaviors and to fit various applications . After describing the joint structure, we detail the kinetostatic analysis to derive the compliant behavior as a function of the design parameters and to prove the variable stiffness ability of the system. Besides, we provide sets of design parameters to match the passive compliance of either a human wrist or ankle. Moreover, to show the versatility of the proposed joint architecture and as guidelines for the future designer, we describe the influence of the main design parameters on the system stiffness characteristic and show the potential of the design for more complex applications. In the last years, articulated soft robots inspired by the musculoskeletal system of vertebrate animals received increased attention from researchers, since they represent promising solutions to enhance the interactions of robots with unknown and dynamic environments, i.e., the real world . In lineactive VSA and the second one as passive VSA  joints that show abilities similar to those of a human joint, such as the same functional range of motion, a variable stiffness mechanism, the overall shape and mass, and so on. Integrating an inherent compliance inside these systems enables us to test both the variable stiffness ability but also the capabilities due to the compliance, such as the possibility of exploiting the natural dynamic of the system  . BesidesUp to now, most of the proposed physically compliant VSAs have only 1 DoF in position . The claOne limitation of physically compliant VSAs is that one mechanical implementation corresponds to one embedded passive behavior. Although there are devices that are human-like in terms of shapes and dimensions, and are able to perform activities of daily living (ADL) , there iIn general, the qualitative representation of the mechanical impedance of human joints is made using stiffness (or compliance) ellipsoids . To moduThe observations on how human beings modulate the stiffness ellipsoids were successfully exploited to implement a teleimpedance controller to generate human-like motions and desired task space impedance . SimilarIn this work, we propose the concept and modeling of a configurable architecture of a physically compliant 2 DoF VSA that can match the passive behavior of either a human wrist or a human ankle. This joint can control its orientations around 2 perpendicular axes and its overall stiffness as a one-dimensional parameter similar to the co-contraction of human muscles. It is based on a state-of-the-art parallel manipulator that we modified to implement an inherent compliance with a compact architecture. Hence, the variable stiffness (VS) ability of the system relies on the antagonistic arrangement of nonlinear elastic actuators . The comBesides the general description of the proposed system in The paper is organized as in the following: α, which is the angular deviation of the link 2 (in red), and by a characteristic length d  on the compliance of the proposed system. To do this study, the compliance of the system should be modeled as a function of these geometric parameters. This is done in α and d , and theα and d are not enough to modulate the compliant behavior of the system , elastic parameters, and internal modulation parameters. As a reminder, there are 5 geometric parameters: Each nonlinear spring can be characterized by nonlinear functions. Their explicit formulations depend on mechanical implementation. They can have various forms such as polynomial functions of degree higher than 2 , trigonometric functions, exponential or hyperbolic functions to name but a few . Therefoλ, stands for the one-dimensional quantity we can use to control the stiffness in the proposed system. Unlike the previous parameters, λ is not fixed to one mechanical implementation and can therefore be different if we try to match several compliant behaviors. Therefore, there is one additional parameter for each desired behavior.The internal modulation parameter, called Therefore, the number of design parameters, noted For this study, we model the nonlinear elastic elements as hyperbolic sine springs for similar reasons as previously described in In this section, we describe the kinetostatic analysis of the proposed system with two goals in mind: (i) to derive the compliance matrix as a function of the design parameters and (ii) to show the variable stiffness ability of the system.Firstly the kinematic analysis done by Z0, namely  and the last three components are the position of its center Define the reference coordinate frame attached to the fixed base of the mechanismd along the axis k in Denoting with A, B, and C) of the mechanism, it is possible to parametrize the configuration of d and α are fixed parameters that define the shared legs geometry, while η is different for each leg.Considering now each leg 2.AccordingThis subsection aims to find the position of all the joints of each leg of the system as a function of the pose of the end effector, Based on the chosen parametrization, calculations for each leg are very similar. Therefore, only generic calculations are presented in the following section. Moreover, using the reduction of parametrization, presented in Firstly, to obtain From Besides that, it can be shown that As The complete solution for a generic leg is thenη with A, namely B and C.It can be easily adapted for each leg, by replacing the generic parameters and variables with the proper ones. For instance, by replacing in the previous equations, f and variable f with respect to The explicit inverse kinematics model is given asf, acting on the end effector, the static equilibrium gives us, using f and the torque of the actuated joints asλ is a scalar real and Using the kinetostatic duality, we obtainTo define the static stiffness, we first need to define Define Therefore, p in f represents only the forces applied on p in the directions x, y and z. This decision is motivated by the fact that, as shown in the previous section, the end-effector of the system has only 2 Dof, which means that the system will not allow motions in one of the three Cartesian directions of space, thus in that same direction the stiffness would be infinite. Therefore its inverse  will be more manageable mathematically, and easier to represent graphically.To represent the stiffness characteristics of the system, we decide to represent in the space its Cartesian compliance, the quantity denoted by p is a function of u and p, from which we obtain in the static equilibriumAccording to the minimal parametrization defined in Moreover, using the definition of the static stiffness of the end effector in The matrix c. This ellipsoid is defined using the singular value decomposition of c. Its axes are directed by the eigenvectors of the matrix and their half lengths are defined by their respective associated eigenvalue. The ellipsoid is centered in p. Hence, the ellipsoid represents the possible deflection of the system in the space for a normalized external wrench, and thus the greater the ellipsoid is, the more compliant is the system.To get a visual representation of the Cartesian compliance, we plot the ellipsoid associated with the matrix y, z)] such as in flattened representation.p is also plotted as a colored area even if the ellipsoids are displayed only in some discrete points. This area is referred to as the workspace of the system. The flattened representation has the advantage not to distort the ellipsoids and not to be sensitive to the Cartesian workspace which may be affected by the design parameters of the mechanism. So, this representation will mainly be used thereafter. Finally, the angular orientation of the axes of the first joint of each leg is plotted as small black lines in the different graphs.The analogous of meridians and parallels have been plotted also to help the understanding of the corresponding ellipses in the example figures. In each representation, the locus of all the possible points reachable of Besides, one thing to notice is that the ellipsoids are only ellipses, tangent to the workspace. This is in agreement with the consideration made at the beginning of this subsection, which motivated the choice of representing the system compliance instead of its stiffness.In this section, we prove that it is possible to have a decoupled control of the position and the stiffness of the system, i.e., that it is possible to modify the spring load without moving the end effector.Let us consider first the static stiffness given in terature .Similarly, the Cartesian compliance of the system defined in Let us prove now that the compliance can be modulated at a fixed position. The first step is to derive a possible expression of X in Therefore, Therefore, the Solutions of A possible definition of Therefore, along the space described by λ defined in λ, as λ, using λ. We can see how, acting on λ, the ellipses scale homogeneously in all directions, without appreciable changes in shape and orientation like the co-contraction of human muscles  position where we observe always a circle for an even distribution of the legs as shown in As it is shown in the different figures, all the design parameters do not have the same effect nor the same intensity on the compliance characteristic of the system. For instance, the effects of λ equal to 0. This means that in absence of external load, no motor torque is required to get the passive behavior of the system. Moreover, we consider an even distribution of the legs around the basis. In this section, we derive sets of parameters to match the passive compliant behavior of a human wrist  and a huIn this work, we proposed and studied a new concept to design a 2 DoF VSA. To reduce the complexity of the mechanical implementation and increase the compactness of the system, we use only 3 motors. This is the minimum number of motors to be able to have a 2 DoF mechanism fully actuated in positions and partially actuated in stiffness. Therefore, our solution is more compact than most of the solutions existing in the current state-of-the-art (refer for instance to the works of ). To theObviously, a limitation of our proposed solution relies in the loss of DoF in the control of stiffness of the system with respect to the existing 2 DoF VSAs. Indeed, our system can control the overall size of its endpoint stiffness ellipse but not its stiffness independently in the two directions of motion. Yet this approach is motivated by the fact that human beings modulate their stiffness through both their posture (exploiting the geometry and properties of their limbs) and co-contraction . More inHowever, the challenge of the mechanical implementation of the passive compliance of human joints remains. That is why we derived a model of our system and studied the effect of its main design parameters on the characteristics of the compliance ellipses. Additionally to the guidelines given in λ equal to 0. As it is shown, this solution may be insufficient. Case 1.2 stands for a solution without any additional constraints. In this case, the two ellipses are well matched. It shows that the system could match additional passive behaviors, for instance by relaxing the constraint of passivity, previously explained . The associated design parameters of these 2 cases are given in For now, biomechanical data exists only at the neutral position of the joints. However, in the future, additional data could be available on various positions of the workspace of the joints. In this case, we may want to match several ellipses. In the proposed system, it is possible to increase the number of desired ellipses. To go further, we could also apply the proposed concept to more complex joints (such as the shoulder or the hip). Unfortunately, such biomechanical data are not yet available. We are more than aware that this is not an easy task and we can only encourage the biomechanical scientific community to pursue their current efforts in this direction, such as the work proposed in λ is free and if λ is set to 0, ensuring thus the passivity of the compliant behavior. Therefore, only the results when λ is null, noted 025, are displayed here. As another further step, we could imagine having a lot of desired ellipses. The case 2.1 for instance corresponds to an isotropic compliant behavior of the system in a large portion of the workspace. Such a system could be conceived for applications using teleoperated robots where we would like to have the same behavior over the workspace. Concretely, the required behavior is now a compliance circle over 25 positions over a grid of 5 × 5 positions between −60° and 60° in both directions. In this case, we have thus 75 characteristics to match. Similar results are obtained if the vectorObviously, in the case of several desired ellipses, there are some mechanical limitations but we can refer to Another limitation of this study is that we did not explore the space of all the possible spring characteristics. Indeed, we used a model (referred to as hyperbolic sine springs) that we already implemented in previous works , as simiThis paper presents the concept of a new configurable 2 DoF variable stiffness joint. The system is based on redundant parallel nonlinear elastic actuation, using the antagonistic approach inspired by the human musculoskeletal system. The kinematic structure of the system is based on the architecture of the Omni-Wrist III, designed by Rosheim et al. and we propose to add in series nonlinear elastic systems to obtain a VSA. To get a compact design, only three motors are used and we prove that this allows us to control both the position and the overall stiffness of system. A one-dimensional quantity linked to the stiffness can thus be controlled like the voluntary co-contraction of human muscles. Moreover, we outline the impact of the main design parameters on the compliant behavior of the system as general guidelines. We describe an optimization methodology to fine-tune the mechanical implementation of this type of system to match the specific passive behavior of a human wrist and ankle.We believe that the proposed design could find many applications, including industrial manipulators and prosthetic devices for various joints, due to its versatility. The sets of parameters obtained to match the passive behavior of a human wrist are particularly relevant as they open the possibility to design a compact system with an embedded passive behavior close to the human one. A new prototype of a compact physically compliant variable stiffness wrist is currently under development.


This retrospective study sought to evaluate the efficacy of transit time flow measurement (TTFM) as a means of predicting bypass graft patency as assessed by coronary artery angiography upon 5-year follow-up.Of 311 patients undergone isolated off-pump coronary artery bypass graft surgery from January 2014 through December 2014, 202 (65%) underwent both intraoperative TTFM and angiography at follow-up. 610 grafts, 202 left internal mammary artery grafts and 408 saphenous vein grafts were checked. Any grafts that exhibited Fitzgibbon type B or O lesions upon angiographic evaluation were considered to be failing. Receiver operating characteristic curves were used to identify the optimal TTFM values for predicting graft patency.P < 0.05). While PI was found to predict LIMA, OM, and PDA graft failure (P < 0.05), it was not associated with the failure of grafts associated with DIAG and PLA vessels. Similarly, DF was found to predict OM and PDA graft failure (P < 0.05), but was not significantly associated with the failure of grafts associated with LIMA, DIAG, or PLA vessels.A total of 610 grafts were included in this analysis, including 202 LIMA grafts and 408 SV grafts, of which 107, 129, 129, and 43 anastomosed to DIAG, OM, PDA, and PLA, respectively. LIMA, DIAG, OM, PDA, and PLA bypass grafts had overall patency rates of 95.0%, 74.8%, 73.6%, 71.5%, and 74.4%, respectively, upon 5-year follow up. No significant differences in TTFM values  were observed when comparing outcomes associated with individual or sequential SV grafting. MGF was found to be predictive of graft failure regardless of the target vessel (LIMA bypass grafts were associated with better 5-year graft patency relative to SV bypass grafts. Similar graft patency rates were observed for both individual and sequential bypass grafts. MGF was able to predict bypass graft failure in patients that underwent off-pump CABG surgery. Coronary artery bypass graft (CABG) surgery outcomes have significantly improved over the last 50 years , with thTTFM is typically used to evaluate intraoperative graft patency in accordance with guidelines published in 2010 , which aFew published studies to date, however, have evaluated the reliability of TTFM as a means of predicting long-term CAG graft patency findings in patients undergoing off-pump CABG surgery. This study was therefore designed to assess the ability of TTFM parameters to predict 5-year postoperative graft patency outcomes in off-pump CABG patients.Between January 2014 and December 2014, 311 total patients underwent isolated off-pump CABG surgery at Beijing Anzhen Hospital, Capital Medical University. Patients included in the present study were those with stable angina, a left ventricle ejection fraction (LVEF) ≥ 50%, and a left ventricular end-diastolic diameter (LVEDD) of ≤ 60 mm.Median sternotomy, standard cannulation, and off-pump procedure stabilizers were employed for the treatment of all patients. Left internal mammary artery (LIMA) grafts were harvested as pedicles, while saphenous vein (SV) grafts were harvested via an open technique. End-to-side anastomoses were conducted in a continuous manner using 6–0 sutures for proximal aortic connections during partial aortic clamping and using 7–0 sutures for the terminal bypass. Side-to-side anti-parallel anastomoses were conducted in a continuous manner using 7–0 sutures for the sequential bypasses.A TTFM  approach was used to measure intraoperative graft flow parameters, including MGF, PI, and the DF. MGF was measured in mL/min, while PI was measured as the difference in peak systolic flow minus peak diastolic flow divided by the median flow and was used to estimate graft resistance. DF was measured as the percentage of the total flow during diastole. These TTFM procedures were recorded intraoperatively immediately prior to sternal closure with the transit-time flowmeter instrument and an appropriately sized probe that was able to fit tightly within the graft without causing compression. Measurements were made when the patient exhibited stable hemodynamics and a mean blood pressure of 70–90 mmHg.After surgery, aspirin  and atorvastatin calcium tablets  were administered to all patients with first 24 h and continued after their discharge, and clopidogrel  was added on the first postoperative day, and continued thereafter for 1 year. Other medications were prescribed as necessary. Postoperative follow-up was obtained via phone call or direct contact with patients or their families, and all patients underwent annual routine clinical assessment. At the 5-year follow-up time point, 28 patients had been lost to follow-up and 81 refused to undergo CAG. The remaining 202 patients (65%) consented to undergo CAG, and therefore were enrolled in our final study.Two or more cardiologists independently analyzed angiographic recordings from each patient that had been collected using standard views, with grafts being assessed as per the Fitzgibbon classification system . Each coP < 0.05 was the significance threshold in this study, and SPSS v25 was used for all statistical testing.Continuous data were given as means ± standard deviation and were compared via unpaired Student’s t-tests. Categorical variables were given as frequencies and percentages, and were compared via chi-squared tests or Fisher’ exact test. Optimal MGF, PI, and DF cut-off values for the prediction of 5-year graft failure were determined using receiver operating characteristic (ROC) curves as the point nearest point to the best point  of these ROC curves. Patient baseline characteristics are compiled in Table In total, 610 total grafts (3.01 grafts/patient) were included in the present study, including 202 LIMA grafts anastomosed to the LAD, and 408 SV grafts that were anastomosed to DIAG, OM, PDA, and PLA in 107, 129, 129, and 43 cases, respectively. A total of 66 patients were bypassed with a single distal SV graft, while 342 distal targets were sequentially bypassed with 141 SV grafts, for a combined total of 408 distal anastomoses with 207 SV graft conduits. Among patients that underwent sequential bypass, 85, 52, and 4 underwent double, triple, and quadruple sequential SV bypass grafting, respectively.No significant differences in TTFM parameters  were observed when comparing individual and sequential SV grafting Table , enablinP < 0.05). While DF were significantly better in all patent OM and PDA grafts relative to occluded OM and PDA grafts (P < 0.05), no significant differences in these values were noted when comparing patent and occluded grafts associated with LIMA, DIAG, and PLA vessels.TTFM values associated with different graft types are shown in Table P = 0.064, 0.137, 0.751, 1, respectively) when comparing individual and sequential grafting.Postoperative 5-year graft patency rates for bypassed grafts in LAD, DIAG, OM, PDA, and PLA vessels were 95.0%, 74.8%, 73.6%, 71.5%, and 74.4%, respectively Fig. . No signP < 0.001) and PI  values were able to predict LIMA graft failure. The optimal MGF cut-off value for predicting 5-year graft failure was found to be 14.5 mL/min, with a sensitivity of 89.6% and a specificity of 80.0%. The optimal PI cut-off value for predicting 5-year graft failure was found to be 3.45 mL/min, with a sensitivity of 91.7% and a specificity of 60.0%.In contrast, DF  offered negligible predictive value for LIMA graft patency rates.ROC curves corresponding to different graft types are shown in Fig. P < 0.05). Optimal MGF cut-off values for DIAG, OM, PDA, and PLA grafts were 14.5 mL/min, 14.5 mL/min, 13.5 mL/min, and 16.5 mL/min, respectively, with respective sensitivity values of 96.8%, 100%, 92.6%, and 95.2%, and with respective specificity values of 75.0%, 76.9%, 93.1%, and 70.0%. While PI was found to offer value as a means of predicting OM and PDA graft failure (P < 0.001), it offered no such predictive value for DIAG and PLA grafts. Similarly, while DF values were able to predict OM and PDA graft failure (P < 0.05), they were unable to predict the failure of DIAG or PLA grafts.For SV grafts, MGF values were found to be predictive of graft failure regardless of the target vessel  and may simply reflect the non-ischemic technique of off-pump coronary surgery.Relatively few studies to date have compared TTFM measurements with angiographic follow-up data, and results from such analyses have been inconsistent. Singh et al.  for examAll LIMA grafts in patients in the present study were anastomosed to the LAD, with an overall 5-year patency rate of 95.0%, while DIAG, OM, PDA, and PLA SV grafts exhibited 5-year patency rates of 74.8%, 73.6%, 71.5%, and 74.4%, respectively. LIMA grafts were associated with better 5-year patency rates relative to SV grafts in the present study. As long-term graft patency is maximized by the use of arterial grafts, and specifically the LIMA , all patWe observed similar patency rates when comparing individual and sequential SV bypass grafts. At present, there is no consensus regarding which of these grafting techniques is optimal. For example, Kim et al. conducted a study of 309 patients that underwent either sequential or individual SV CABG surgery, and concluded that sequential bypass grafting was associated with higher mean flow rates and with better mid-term patency relative to individual grafting . This isHerein we calculated optimal TTFM cut-off values for assessing graft failure risk in patients undergoing off-pump CABG surgery. For LIMA grafts, an MGF cut-off value of 14.5 mL/min was found to be able to strongly predict graft patency (AUC = 0.875).at the same time, a PI cut-off value of 3.45 offered a moderate ability for LIMA grafts (AUC = 0.725). For DIAG, OM, PDA, and PLA grafts, we calculated optimal MGF cut-off values of 14.5 mL/min (AUC = 0.921), 14.5 mL/min (AUC = 0.935), 13.5 mL/min (AUC = 0.956), and 16.5 mL/min (AUC = 0.905), respectively. PI cut-off values for SV grafts were inconsistent. However, there are so many factors affecting flow in a bypass graft. Such as: size, length, quality of conduit and of native artery, run-off quality of the coronary bed, mean arterial pressure, heart rate, competitive flow, viscosity of the blood. As we described in the article, the specificity of cut-off MGF value of LIMA, DIAG, OM, PDA, PLA was 80%, 75%, 77%, 93% and 70%, respectively. The threshold of diagnostic accuracy was relatively low, so the cut-off MGF value is insufficient to guide clinical practice. Our study suggests that grafts are obviously not patent by TTFM should be revised.There are certain limitations to this study. For one, it was retrospective in nature rather than a randomized controlled trial. In addition, the sample size in the present study was small, and all off-pump CABG surgeries described herein were conducted at a single center. In addition, the measurements taken during surgery may not truly reflect the capacity of a given graft to carry flow, as these measurements can be influenced by many factors including cardiac recovery and graft spasm. Most of all, many factors affecting graft patency over time is this length of time passed before angiographic assessment.MGF was able to predict rates of 5-year LIMA and SV graft failure in patients undergoing off-pump CABG surgery. Our study suggests that grafts are obviously not patent by TTFM should be revised.