Long-term Outcomes Following Colectomy and Liver Transplantation for Inflammatory Bowel Disease with Primary Sclerosing Cholangitis.

OBJECTIVE: To investigate the long-term outcomes of patients with combined primary sclerosing cholangitis/inflammatory bowel disease (PSC-IBD) undergoing both liver transplantation (LT) and total abdominal colectomy (TAC). SUMMARY BACKGROUND DATA: The fraction of patients with PSC-IBD that require both LT and TAC is small, thereby limiting significant conclusions regarding long-term outcomes. METHODS: Adult and pediatric patients from nine centers from the US IBD Surgery Collaborative who underwent staged LT and TAC for PSC-IBD were included. Long-term outcomes, including survival, were assessed. RESULTS: Among 127 patients, 66 underwent TAC-before-LT, with a median time from TAC to LT of 7.9 yrs, while 61 underwent LT-before-TAC, with a median time from LT to TAC of 4.4 years. Median patient survival post TAC was significantly worse in those undergoing LT-before-TAC (16.0 yrs vs. 42.6 yrs, P=0.007), while post LT survival was not impacted by the order of TAC and LT (21.6 yrs vs. 22.0 yrs, P=0.81). Patients undergoing TAC for medically refractory disease had a higher incidence of recurrent PSC (rPSC) (P=0.02) and biliary complications (0.09) compared to those undergoing TAC for oncologic indications. Definitive TAC reconstruction with either end ileostomy or ileal-pouch anal anastomosis (IPAA) did not impact post-LT or post-TAC outcomes. CONCLUSIONS: Long term survival in PSC-IBD was contingent upon progression to LT and was not impacted by the need for TAC. PSC-IBD patients undergoing TAC for medically refractory disease had a higher incidence of rPSC and biliary complications. The use of IPAA in PSC-IBD was a viable alternative to end ileostomy.

Takotsubo cardiomyopathy following liver transplantation - a multicenter cohort study.

OBJECTIVE: Takotsubo cardiomyopathy (TCM) is an acute, stress-mediated, reversible cardiomyopathy that occurs in the absence of hemodynamically significant coronary artery disease. We aimed to investigate the characteristics and outcomes of patients who developed TCM following liver transplantation (LT) in a multicenter study. METHODS: Adult patients from six centers across the US who developed TCM according to Mayo Clinic criteria following LT between 2008-2023 were included. Demographics, perioperative and long-term outcomes, and treatment modalities were assessed. RESULTS: Fifty-five patients were included. The center incidence of TCM ranged from 0.1 - 0.5%. The majority were female (54.5%) and Caucasian (87.2%), and median age at transplant was 59 years. The primary etiologies for LT were alcohol-related cirrhosis (49.1%) and metabolic dysfunction-associated steatotic liver disease cirrhosis (21.8%). The median time from LT to TCM diagnosis was 4 days. TCM was associated with a 60.9% reduction in left ventricular ejection fraction (LVEF) from a pretransplant median LVEF of 64.0% to 25.0%. The most common treatment for TCM was diuretics (67.3%) and afterload reduction (54.5%), with only 27.3% of patients requiring vasopressor support. At median follow-up 31.5 months, 1-year and 3-year overall survivals were 86.3% and 69.4%, respectively. Repeat echocardiogram performed at a median of 84 days demonstrated 45/55 patients (81.8%) had recovered LVEF ≥50%. Patients with LVEF recovery to ≥50% had significantly improved overall survival (OS) compared to those without LVEF recovery >50% (106.4 mos vs. 12.2 mos, p=0.001). CONCLUSION: TCM following LT is associated with a significant reduction in LVEF, however the majority of patients recover LVEF to > 50% with minimal perioperative mortality. Importantly, follow-up assessment of LVEF has significant implications as lack of recovery is associated with worse OS.

Superbunched Radiation of a Tunnel Junction due to Charge Quantization.

A chaotic light source is characterized by the fact that many independent emitters radiate photons with a random optical phase. This is similar compared to a tunnel junction where many independent channels are able to emit photons due to a coupling to an electromagnetic environment. However, in a recent experiment it has been observed that a tunnel junction can deviate from the expectation of chaotic light and is able to emit strongly correlated, superbunched photons. Motivated by this, we study the correlation of the radiation and show that the superbunching originates from the emission of multiple photons which is possible due to the quantization of charge.

Exploring the relationships between pathogen-specific prenatal infections requiring inpatient admission and domains of offspring behaviour at age 5.

BACKGROUND: Research exploring the relationship between prenatal infection and child behavioural outcomes would benefit from further studies utilising full-population samples with the scale to investigate specific infections and to employ robust designs. We tested the association among several common infections requiring inpatient admission during and after pregnancy with a range of childhood behavioural outcomes, to determine whether any negative impact was specific to the period of foetal development. METHODS: The sample included all mother-offspring pairs from the Australian state of New South Wales (NSW) for whom the child commenced their first year of full-time schooling in 2009 (~age 5 years; n = 77,302 offspring), with records linked across four health administrative data sets including the NSW perinatal data collection (PDC), the NSW admitted patient data collection (APDC) and the NSW component of the 2009 Australian Early Development Census (AEDC). Multivariable linear regression was used to test associations between a number of infections requiring inpatient admission during and after pregnancy with a range of teacher assessed behavioural outcomes. RESULTS: Associations specific to the prenatal period were only found for streptococcus A although this would need to be reproduced in external samples given the low prevalence. Otherwise, 12 out of 15 selected infections either showed no association prenatally or also demonstrated associations in the 12 months after pregnancy. For example, prenatal hepatitis C, influenza and urinary E. coli infections were associated with lower scores of several domains of childhood behaviour, but even stronger associations were found when these same maternal infections occurred after pregnancy. CONCLUSIONS: The prenatal infections we tested appeared not to impact childhood behaviour by altering foetal neurodevelopment. Rather, the strong associations we found among infections occurring during and after pregnancy point to either residual socioeconomic/lifestyle factors or a shared familial/genetic liability between infections and behavioural problems.

Iscalimab Combined With Transient Tesidolumab Prolongs Survival in Pig-to-Rhesus Monkey Renal Xenografts.

OBJECTIVE: To evaluate the clinically relevant anti-CD40 antibody iscalimab for baseline immunosuppression in a preclinical pig-to-rhesus renal xenograft model. SUMMARY BACKGROUND DATA: CD40/CD40L co-stimulation blockade-based immunosuppression has been more successful than calcineurin-based protocols in prolonging xenograft survival in preclinical models. METHODS: GGTA1 knockout/CD55 transgenic pig kidneys were transplanted into rhesus monkeys (n = 6) receiving an iscalimab-based immunosuppressive regimen. RESULTS: Two grafts were lost early (22 and 26 days) because of ectatic donor ureters with otherwise normal histology. The other recipients survived 171, 315, 422, and 439 days with good renal function throughout the posttransplant course. None of the recipients experienced serious infectious morbidity. CONCLUSIONS: It may be reasonable to evaluate an iscalimab-based immunosuppressive regimen in clinical renal xenotransplantation.

Risk of metachronous colorectal cancer associated with polypectomy during endoscopic diagnosis of colorectal cancer.

BACKGROUND AND AIM: There are conflicting reports regarding the risk of metachronous colorectal cancer (CRC) subsequent to colonoscopy with polypectomy or biopsy performed concurrently with diagnostic biopsies for CRC. We aimed to establish the 5-year risk of CRC in patients who had synchronous polypectomy or biopsies during the colonoscopy at which CRC was diagnosed. METHODS: This is a single-centre retrospective case-control study of adults who underwent surgical resection for CRC over a 2-year period (January 2016 to December 2017). Colonoscopy details of interest were the location of the CRC, polypectomy and non-CRC biopsy sites. In patients with CRC at index colonoscopy, we sought associations between the occurrence of metachronous CRC and the sites from which endoscopic specimens had been obtained. RESULTS: Our study population comprised 225 patients with a median (IQR) age of 71 (60-77) years. Polypectomy or biopsy at a non-CRC site had been performed during the index colonoscopy in 108 patients (48%), including 83 (37%) polypectomies outside the surgical resection field. There were 8 (3.6%) metachronous CRCs: 1 (0.4%) at the site of endoscopic mucosal resection for a 15-mm sessile serrated lesion, 3 (1.3%) anastomotic site CRCs and 4 (1.8%) at other sites within the colon. There was no significant difference in the prevalence of metachronous CRC in patients who underwent polypectomy/biopsy at the index colonoscopy compared with those who did not (1.9% vs. 5.1%, p = 0.283). CONCLUSION: There was no significant increased risk of metachronous CRC subsequent to synchronous polypectomy or biopsy during the colonoscopy at which CRC was diagnosed.

Using latent variable modelling to identify etiological heterogeneity in preterm delivery.

AIMS: To identify a subgroup of mothers at high risk of preterm delivery, defined by empirical classes of multimorbidity and recurrence across three consecutive births. METHODS: The data were extracted from the perinatal data collection (PDC) of all inpatient live births (n = 435 912) occurring in the Australian state of Queensland between January 2009 and December 2015. Within this data, a total of 7714 primiparous mothers delivered three consecutive singleton live births (total births = 23 142), and comprise the sample for all analyses. RESULTS: The LCA indicated a four-class solution fit the data best at each time point, including (i) a 'normative' or healthy class with little morbidity (including >80% of the sample at each birth); (ii) a preterm, high morbidity class (<2% of the sample); (ii) a delivery morbidity class (4-8% of the sample); and (iii) preterm, low morbidity class (5-6% of the sample). Each group exhibited unique and consistent associations with maternal and pregnancy-related factors across births. After accounting for these factors, the high morbidity class and preterm, low morbidity class strongly predicted these same classes across consecutive births, and from birth 1 to birth 3 (second-order transition). CONCLUSIONS: A small but highly morbid class of neonatal deliveries emerged, exhibiting strong continuity across consecutive births (odds ratios >10), independent of a range of maternal and pregnancy-related factors. This group of women, if subject to further investigation, could provide valuable insight into the aetiology of prematurity and associated morbidity, perhaps providing information to improve birth outcomes among all women.

Liver Transplantation as a New Standard of Care in Patients With Perihilar Cholangiocarcinoma? Results From an International Benchmark Study.

OBJECTIVE: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. BACKGROUND: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. METHODS: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. RESULTS: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001). CONCLUSION: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.

Organ donation after self-inflicted injury: A single institution analysis.

BACKGROUND: This study sought to determine the contribution of self-inflicted injury-related deaths to local organ donation rates and analyze contributing factors. METHODS: A retrospective review of adult patients with traumatic self-inflicted injuries was performed at a Level I trauma center from 2013 to 2017. Data were obtained from the institutional trauma registry and cross-referenced with the local organ procurement organization (OPO). Referral rates were analyzed and outcomes, demographics and injury characteristics were compared between patients who underwent donation versus those who did not. RESULTS: 142 adult patients presented with traumatic self-inflicted injury, and 100 (70.4%) had referral calls made to the local OPO. These patients were predominantly male (83%), and gunshot injuries accounted for 75% of all mechanisms. Sixty-four percent had organ referrals versus tissue referrals (34%), and 17 (26.6%) of those patients went on to donate. The median number of organs procured was 4 [IQR 0-5]. In multivariate analysis, for each year increase in age, patients were less likely to have an organ referral (OR = .96 [95% CI .93-.99]; p = .0134) and less likely to undergo donation (OR = .95 [95% CI .90-.99]; p = .0308). CONCLUSIONS: Self-inflicted injury, though tragic, may provide a significant contribution to the limited organ donor registry.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

OBJECTIVE: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). SUMMARY OF BACKGROUND DATA: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. METHODS: The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). RESULTS: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). CONCLUSIONS: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Logistic Regression Models with Unspecified Low Dose-Response Relationships and Experimental Designs for Hormesis Studies.

Hormesis refers to a nonmonotonic (biphasic) dose-response relationship in toxicology, environmental science, and related fields. In the presence of hormesis, a low dose of a toxic agent may have a lower risk than the risk at the control dose, and the risk may increase at high doses. When the sample size is small due to practical, logistic, and ethical considerations, a parametric model may provide an efficient approach to hypothesis testing at the cost of adopting a strong assumption, which is not guaranteed to be true. In this article, we first consider alternative parameterizations based on the traditional three-parameter logistic regression. The new parameterizations attempt to provide robustness to model misspecification by allowing an unspecified dose-response relationship between the control dose and the first nonzero experimental dose. We then consider experimental designs including the uniform design (the same sample size per dose group) and the c -optimal design (minimizing the standard error of an estimator for a parameter of interest). Our simulation studies showed that (1) the c -optimal design under the traditional three-parameter logistic regression does not help reducing an inflated Type I error rate due to model misspecification, (2) it is helpful under the new parameterization with three parameters (Type I error rate is close to a fixed significance level), and (3) the new parameterization with four parameters and the c -optimal design does not reduce statistical power much while preserving the Type I error rate at a fixed significance level.

Toxoplasma gondii induces prolonged host epidermal growth factor receptor signalling to prevent parasite elimination by autophagy: Perspectives for in vivo control of the parasite.

Toxoplasma gondii causes retinitis and encephalitis. Avoiding targeting by autophagosomes is key for its survival because T. gondii cannot withstand lysosomal degradation. During invasion of host cells, T. gondii triggers epidermal growth factor receptor (EGFR) signalling enabling the parasite to avoid initial autophagic targeting. However, autophagy is a constitutive process indicating that the parasite may also use a strategy operative beyond invasion to maintain blockade of autophagic targeting. Finding that such a strategy exists would be important because it could lead to inhibition of host cell signalling as a novel approach to kill the parasite in previously infected cells and treat toxoplasmosis. We report that T. gondii induced prolonged EGFR autophosphorylation. This effect was mediated by PKCα/PKCß âž” Src because T. gondii caused prolonged activation of these molecules and their knockdown or incubation with inhibitors of PKCα/PKCß or Src after host cell invasion impaired sustained EGFR autophosphorylation. Addition of EGFR tyrosine kinase inhibitor (TKI) to previously infected cells led to parasite entrapment by LC3 and LAMP-1 and pathogen killing dependent on the autophagy proteins ULK1 and Beclin 1 as well as lysosomal enzymes. Administration of gefitinib (EGFR TKI) to mice with ocular and cerebral toxoplasmosis resulted in disease control that was dependent on Beclin 1. Thus, T. gondii promotes its survival through sustained EGFR signalling driven by PKCα/ß âž” Src, and inhibition of EGFR controls pre-established toxoplasmosis.

Epigenetic reprogramming in periodontal disease: Dynamic crosstalk with potential impact in oncogenesis.

Periodontitis is a chronic multifactorial inflammatory disease associated with microbial dysbiosis and characterized by progressive destruction of the periodontal tissues. Such chronic infectious inflammatory disease is recognized as a major public health problem worldwide with measurable impact in systemic health. It has become evident that the periodontal disease phenotypes are not only determined by the microbiome effect, but the extent of the tissue response is also driven by the host genome and epigenome patterns responding to various environmental exposures. More recently there is mounting evidence indicating that epigenetic reprogramming in response to combined intrinsic and environmental exposures, might be particularly relevant due its plasticity and potential application towards precision health. The complex epigenetic crosstalk is reflected in the prognosis and progress of periodontal diseases and may also lead to a favorable landscape for cancer development. This review discusses epigenomics modifications focusing on the role of DNA methylation and pathways linking microbial infection and inflammatory pathways, which are also associated with carcinogenesis. There is a more clear vision whereas 'omics' technologies applied to unveil relevant epigenetic factors could play a significant role in the treatment of periodontal disease in a personalized mode, evidencing that public health approach should coexist with precision individualized treatment.

Angptl4 does not control hyperglucagonemia or α-cell hyperplasia following glucagon receptor inhibition.

Genetic disruption or pharmacologic inhibition of glucagon signaling effectively lowers blood glucose but results in compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Ben-Zvi et al. recently reported that angiopoietin-like protein 4 (Angptl4) links glucagon receptor inhibition to hyperglucagonemia and α-cell proliferation [Ben-Zvi et al. (2015) Proc Natl Acad Sci USA 112:15498-15503]. Angptl4 is a secreted protein and inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. We report that Angptl4-/- mice treated with an anti-glucagon receptor monoclonal antibody undergo elevation of plasma glucagon levels and α-cell expansion similar to wild-type mice. Overexpression of Angptl4 in liver of mice caused a 8.6-fold elevation in plasma triglyceride levels, but did not alter plasma glucagon levels or α-cell mass. Furthermore, administration of glucagon receptor-blocking antibody to healthy individuals increased plasma glucagon and amino acid levels, but did not change circulating Angptl4 concentration. These data show that Angptl4 does not link glucagon receptor inhibition to compensatory hyperglucagonemia or expansion of α-cell mass, and that it cannot be given to induce such secretion and growth. The reduction of plasma triglyceride levels in Angptl4-/- mice and increase following Angptl4 overexpression suggest that changes in plasma triglyceride metabolism do not regulate α-cells in the pancreas. Our findings corroborate recent data showing that increased plasma amino acids and their transport into α-cells link glucagon receptor blockage to α-cell hyperplasia.

Donor-specific antibodies in liver transplantation: challenges in diagnosis and determining clinical impact.

PURPOSE OF REVIEW: Our understanding of the clinical impact of donor-specific antibodies in liver transplant recipients has evolved in recent years as outcomes for liver allografts have improved and advances in diagnostic testing have made recognition of antibody mediated rejection in transplant patients more sensitive. RECENT FINDINGS: Two main types of donor-specific antibodies - preformed and de novo - have been reported in the literature to have a negative impact on graft survival, and researchers have been able to further identify subclasses of class II donor-specific antibodies as being the most clinically impactful. Furthermore, there is evidence that donor-specific antibody formation can augment cellular rejection in liver grafts and lead to worsened clinical outcomes. Recent data have shown a higher prevalence of donor-specific antibody formation than previously reported. SUMMARY: This review explores the most recent literature regarding the clinical impact of both preformed and de-novo donor-specific antibodies and potential management guidelines for patients undergoing liver transplantation. The best practice guidelines for undergoing monitoring for donor-specific antibody formation and protocol biopsies in sensitized patients will depend on further multiinstitutional studies.

Long-term survival of pig-to-rhesus macaque renal xenografts is dependent on CD4 T cell depletion.

The shortage of available organs remains the greatest barrier to expanding access to transplant. Despite advances in genetic editing and immunosuppression, survival in experimental models of kidney xenotransplant has generally been limited to <100 days. We found that pretransplant selection of recipients with low titers of anti-pig antibodies significantly improved survival in a pig-to-rhesus macaque kidney transplant model (6 days vs median survival time 235 days). Immunosuppression included transient pan-T cell depletion and an anti-CD154-based maintenance regimen. Selective depletion of CD4+ T cells but not CD8+ T cells resulted in long-term survival (median survival time >400 days vs 6 days). These studies suggested that CD4+ T cells may have a more prominent role in xenograft rejection compared with CD8+ T cells. Although animals that received selective depletion of CD8+ T cells showed signs of early cellular rejection (marked CD4+ infiltrates), animals receiving selective CD4+ depletion exhibited normal biopsy results until late, when signs of chronic antibody rejection were present. In vitro study results suggested that rhesus CD4+ T cells required the presence of SLA class II to mount an effective proliferative response. The combination of low pretransplant anti-pig antibody and CD4 depletion resulted in consistent, long-term xenograft survival.

Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis.

AIMS: Atrial fibrosis contributes to arrhythmogenesis in atrial fibrillation and can be detected by MRI or electrophysiological mapping. The current study compares the spatial correlation between delayed enhancement (DE) areas to low-voltage areas (LVAs) and to arrhythmogenic areas with spatio-temporal dispersion (ST-Disp) or continuous activity (CA) in atrial fibrillation (AF). METHODS AND RESULTS: Sixteen patients with persistent AF (nine long-standing) underwent DE-magnetic resonance imaging (1.25 mm × 1.25 mm × 2.5 mm) prior to pulmonary vein isolation. Left atrial (LA) voltage mapping was acquired in AF and the regional activation patterns of 7680 AF wavelets were analysed. Sites with ST-Disp or CA were characterized (voltage, duration) and their spatial relationship to DE areas and LVAs <0.5 mV was assessed. Delayed enhancement areas and LVAs covered 55% and 24% (P < 0.01) of total LA surface, respectively. Delayed enhancement area was present at 61% of LVAs, whereas low voltage was present at 28% of DE areas. Most DE areas (72%) overlapped with atrial high-voltage areas (>0.5 mV). Spatio-temporal dispersion and CA more frequently co-localized with LVAs than with DE areas (78% vs. 63%, P = 0.02). Regional bipolar voltage of ST-Disp vs. CA was 0.64 ± 0.47 mV vs. 0.58 ± 0.51 mV. All 28 ST-Disp and 56 CA areas contained electrograms with prolonged duration (115 ± 14 ms) displaying low voltage (0.34 ± 0.11 mV). CONCLUSION: A small portion of DE areas and LVAs harbour the arrhythmogenic areas displaying ST-Disp or CA. Most arrhythmogenic activities co-localized with LVAs, while there was less co-localization with DE areas. There is an important mismatch between DE areas and LVAs which needs to be considered when used as target for catheter ablation.

Effect of pore size in bone regeneration using polydopamine-laced hydroxyapatite collagen calcium silicate scaffolds fabricated by 3D mould printing technology.

OBJECTIVE: The pore size of the scaffold is a critical factor in repairing large bone defect. Here, we investigated the potential of bone regeneration using novel nanocomposite polydopamine-laced hydroxyapatite collagen calcium silicate (HCCS-PDA) scaffolds with two different pore sizes, 250 and 500 µm. SAMPLES/SETTING: A total of 12 male Sprague-Dawley rats were implanted with HCCS-PDA scaffold with pore size of either 250 or 500 µm into surgically created critical-sized defect (CSD). METHODS: HCCS-PDA scaffolds were fabricated using mould printing technique. The effect of pore size on mechanical strength of the scaffolds was assessed by compression testing. After seeding with rat mesenchymal stem cells (rMSCs), the scaffolds were implanted, and new bone formation was evaluated using microCT and histomorphometric analysis after 8 weeks. RESULTS: MicroCT and histology analysis demonstrated restricted peripheral new bone formation in either dural or periosteal side and limited new bone formation in the 250 µm pore scaffold. Conversely, the 500-µm pore scaffold showed more penetration of new bone into the scaffold and greater bone regeneration in the rat CSD. CONCLUSION: Based on our results, which demonstrated improved new bone formation in 500 µm pores scaffold, we can conclude that effective scaffold pore size that induces osteointegration and bone regeneration is around 500 µm for HCCS-PDA nanocomposite scaffold.