Prophylactic anti-reflux procedure for children undergoing laparoscopic gastrostomy: Rethinking of the routine practice.

AIM: Laparoscopic gastrostomy is a frequently performed procedure in children requiring long-term enteral nutrition. The role of prophylactic anti-reflux surgery during gastrostomy placements is controversial. The current study aims to evaluate the role of prophylactic anti-reflux procedures during gastrostomy placement. METHODS: A retrospective single-center analysis of all children without reflux receiving laparoscopic gastrostomy from January 2005 through December 2021 was performed. Demographics and clinical outcomes were compared between patients receiving gastrostomy placement alone and patients receiving gastrostomy with prophylactic anti-reflux surgery. RESULTS: A total of 79 patients had a confirmed absence of reflux by a 24-h pH/impedance study before operation. Thirty-six of these patients underwent prophylactic anti-reflux surgery (PAR) while 43 received gastrostomy (PG) alone. The operative time and conversion rate were significantly higher in the PAR group (140.5 ± 67.5 vs. 80.2 ± 66.8 min, p = 0.0001 and 8.3% vs. 0%, p = 0.04). There were no major complications in either group. De novo reflux was detected in five patients (11.6%) in the PG group. None of these patients progressed to require anti-reflux surgery. CONCLUSION: The occurrence of de novo reflux after laparoscopic gastrostomy was low and could be managed without anti-reflux surgery. A routine pre-operative pH study is helpful for appropriate patient selection to avoid unnecessary anti-reflux surgery, which lengthens operative time and increases the conversion rate.

Quality of Life in Long-Term Survivors of Surgical Necrotizing Enterocolitis.

OBJECTIVE: This study evaluated the quality of life (QoL) in patients who have recovered from surgical necrotizing enterocolitis (NEC). METHODS: This is a cross-sectional study conducted in a tertiary centre and patients who have received surgery for NEC between 2000 and 2014 were invited to participate. The Pediatric Quality of Life Inventory Generic (PedsQL™) Core Scale Version 4.0 was used as the assessment tool. Values were reported as median (interquartile rage) and compared with age-matched controls. RESULTS: During the study period, 90 patients were eligible for the study and 29 patients have completed the survey. There was no gender difference and the median age was 10 years (9-13 years). Nine patients have suffered from short bowel syndrome (SBS) as a result of the surgery. For the QoL assessment, 17 participants have completed both parent proxy and child-rated survey; 11 completed the parent-rated survey and 1 completed child-rated survey only. The scores for parent-rated survey were - overall: 86.4 (70.7-92.7); physical: 95.3 (83.6-100) and psychosocial: 82.5 (66.3-90.4). The scores for child-rated survey were - overall: 82.1 (73.4-96.2); physical: 96.9 (90.6-99.2) and psychosocial: 81.7 (64.2-95.8). Regarding the impact of previous SBS on the QoL, there were no significant difference in the overall score for both parent proxy and child-rated survey (SBS-ve vs + ve) (parent-rated: 87.5 vs 85.3, p = 0.849; child-rated: 81.0 vs 88.0, p = 0.503). There were also no differences in physical and psychosocial assessments (parent-rated: [physical] 95.3 vs 95.3, p = 0.267; [psychosocial] 84.2 vs 80.0, p = 0.274; child-rated: [physical] 95.3 vs 96.9, p = 0.395; [psychosocial] 79.2 vs 87.5, p = 0.611). CONCLUSION: The QoL in long-term survivors of surgical NEC without major medical illnesses is comparable to normal population. However, they may have a lower psychosocial well-being that should be addressed. Previous history of SBS does not have a significant impact on the future QoL. LEVEL OF EVIDENCE: III.

Open Versus Thoracoscopic Repair of Congenital Diaphragmatic Hernia: A 19-Year Review in a Tertiary Referral Centre in Hong Kong.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a developmental defect that causes herniation of abdominal organs into the thoracic cavity with significant morbidity. Thoracoscopic repair of CDH is an increasingly prevalent yet controversial surgical technique, with limited long-term outcome data in the Asian region. The aim of this study was to compare open laparotomy versus thoracoscopic repair of CDH in paediatric patients in a major tertiary referral centre in Asia. METHODS: We performed a retrospective analysis of neonatal patients who had open laparotomy or thoracoscopic repair for CDH in our institution between July 2002 and November 2021. Demographic data, perioperative parameters, recurrence rates and surgical complications were analysed. RESULTS: 64 patients were identified, with 54 left sided CDH cases. 33 patients had a prenatal diagnosis and 35 patients received minimally invasive surgical repair. There was no significant difference between open and minimally invasive repair in recurrence rate (13 % vs 17 %, P = 0.713), time to recurrence (184 ± 449 days vs 81 ± 383 days, P = 0.502), or median length of ICU stay (11 ± 14 days vs 13 ± 15 days, P = 0.343), respectively. Gastrointestinal complications occurred in 7 % of neonates in the open group and none in the thoracoscopic group. Median follow-up time was 9.5 years. CONCLUSIONS: This study is a large congenital diaphragmatic hernia series in Asia, with long term follow-up demonstrating no significant difference in recurrence rate, time to recurrence or median length of ICU stay between open and minimally invasive repair, suggesting thoracoscopic approach is a non-inferior surgical option with avoidance of gastrointestinal complications compared to open repair. TYPE OF STUDY: Retrospective Cohort Study.

The impact of pre-operative cholecystostomy on laparoscopic excision of choledochal cyst in paediatric patients.

PURPOSE: This aim of this study was to identify the pre-operative risk factors for conversion during laparoscopic excision of choledochal cyst in paediatric patients. METHODS: A retrospective single-centre study was carried out. All paediatric patients (< 18 years) who had undergone laparoscopic excision of choledochal cyst between 2004 and 2021 were reviewed. The outcome was conversion to open surgery and pre-operative factors that affected the conversion rate were analyzed. RESULTS: Sixty-one patients were included. Conversion was required in 24 cases (39.3%). There was no difference in the conversion rate between the first (before 2012, n = 30) and second (after 2012, n = 31) half of the series (36.7% vs. 42.0%, p = 0.674). Majority was type 1 cyst (86.8%) and the median cyst size was 4.6 cm (IQR: 2.2-6.4 cm). Antenatal diagnosis was available in 18 patients (29.5%). The median age at operation was 23.0 months (IQR: 8.0-72.0 months). Pre-operatively, 19 patients (31.1%) suffered from cholangitis and 5 (8.2%) of them required cholecystostomy. Comparing patients with successful laparoscopic surgery (L) and converted cases (C), there were no differences in the age at operation (p = 0.74), cyst size (p = 0.35), availability of antenatal diagnosis (p = 0.23) and cholangitic episodes (p = 0.40). However, a higher percentage of patients required cholecystostomy in the converted group (L vs. C = 2.7% vs. 16.7%, p = 0.05). Using logistic regression analysis, it was also a risk factor for conversion (OR = 3.5 [1.37-5.21], p = 0.05). CONCLUSION: Pre-operative cholecystostomy is a potential risk factor for conversion during laparoscopic excision of choledochal cyst in children.

Analysing Factors Prolonging Hospital Stay After Excision of Choledochal Cyst-A Pathway Towards Enhanced Recovery After Surgery.

BACKGROUND: To evaluate factors affecting length of stay (LOS) after choledochal cyst resection in paediatric patients. METHODS: This was a retrospective study on patients operated between 2004 and 2021. Associations between clinical factors and LOS were evaluated by bivariate analysis, multiple regression, and equivalence test. RESULTS: Sixty-two patients were included. Twenty-four underwent hepaticoduodenostomy as biliary reconstruction. Five suffered from major complications. The median (25th-75th percentile) operation time was 279 (182-378) min. Median LOS, time to enteral feeding, and time to abdominal drain removal were 8(6-10), 2(1-3), and 5(4-7) days, respectively. Seven factors were found significantly associated with a shorter LOS in bivariate analysis and were included in multiple regression. It revealed that early abdominal drain removal (p < 0.001), early enteral feeding (p = 0.042), and the absence of major complications (p < 0.001) were significantly associated with shorter LOS. Equivalence test suggested that age and preoperative cholangitis had no practical effect on LOS. CONCLUSIONS: Early enteral feeding, early drain removal, and avoidance of major complications are associated with a shorter LOS.

Silver nanoparticles promote osteogenic differentiation of mouse embryonic fibroblasts in vitro.

OBJECTIVE: This study investigated if silver nanoparticles (AgNps) could promote the proliferation and osteogenic differentiation of mouse embryonic fibroblasts. METHODS: Mouse embryonic fibroblasts were divided into two groups: Group 1 cells were cultured in DMEM/F12 medium and Group 2 cells were cultured in osteogenic medium. Both groups were then treated with 16, 32, or 100 µM AgNps. Fibroblast proliferation and viability were measured using BrdU and MTT methods at varying time points. Alizarin red staining and alkaline phosphatase (ALP) activity were measured to observe fibroblast differentiation into osteoblasts. Proteomics (cytokine array) was used to detect 111 different cytokines during differentiation. RESULTS: AgNps stimulated proliferation of mouse embryonic fibroblasts at a concentration of 16 µM. Marked enhancement of calcium mineralization was observed in cells cultured with AgNps compared with cells cultured without AgNps. Group 2 cells displayed nodules around the center where the cell density was high. ALP activity of mouse embryonic fibroblasts cultured in osteogenic medium increased during the whole culture period. Addition of AgNps at concentrations of 32 µM and 100 µM induced higher ALP activity at days 7 and 14. Proteomic array results show that low density lipoprotein receptor (LDL-R) and proprotein convertase subtilisin/kexin type 9 (PCSK-9) were significantly increased, while osteoprotegerin (OPG) was significantly reduced in medium containing 16 µM AgNPs. CONCLUSION: AgNps could promote differentiation of mouse embryonic fibroblasts into osteoblastic cells. LDL-R and PCSK-9, as well as OPG, may play a critical role in this process.

Direct cellular reprogramming and transdifferentiation of fibroblasts on wound healing-Fantasy or reality?

Induced pluripotent stem cell (iPSC) technology is one of the de novo approaches in regeneration medicine and has led to new research applications for wound healing in recent years. Fibroblasts have attracted wide attention as the first cell line used for differentiation into iPSCs. Researchers have found that fibroblasts can be induced into different types of cells in variable mediums or microenvironments. This indicates the potential "stem" characteristics of fibroblasts in terms of direct cellular reprogramming compared with the iPSC detour. In this review, we described the morphology and biological function of fibroblasts. The stem cell characteristics and activities of fibroblasts, including transdifferentiation into myofibroblasts, osteogenic cells, chondrogenic cells, neurons, and vascular tissue, are discussed. The biological values of fibroblasts are then briefly reviewed. Finally, we discussed the potential applications of fibroblasts in clinical practice.

Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.

Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis.

Identification of cancer-related genes FGFR2 and CEBPB in choledochal cyst via RNA sequencing of patient-derived liver organoids.

BACKGROUND: Choledochal cysts (CC) are congenital bile duct anomalies with 6-30% risk for developing bile duct cancer. However, the molecular mechanisms underlying cancer risk of CC are unknown. We sought to identify the gene expression changes underlying the cancer risk of CC patients. METHODS: Liver organoids (n = 51) were generated from liver/bile duct biopsies of CC (n = 7; type I) and hepatoblastoma (n = 5; HB: non-tumor & tumor) for RNA sequencing. Bioinformatics analysis was conducted to identify differentially expressed cancer-related genes in CC and controls. We compared CC with non-cancerous and cancerous controls, normal adjacent non-tumor region of hepatoblastoma (HB) liver as non-cancerous control and tumor region as non-CC cancer control (HB-tumor). Reverse transcription real-time quantitative PCR (RT-qPCR) verification and immunohistochemistry of selected genes was conducted in additional CC and HB liver biopsies. FINDINGS: HB non-tumor and HB tumor organoids displayed distinct gene expression profiles. Expression profiling separated CC organoids into two clusters, one overlapping with HB non-tumor and the other one with HB tumor organoids. Genes selected based on their log2FoldChange values for RT-qPCR verification in 31 CC and 11 HB non-tumor liver tissues revealed significantly elevated expression of FGFR2 in 7 and CEBPB in 2 CC liver tissues (CC vs HB: 4.082 vs. 0.7671, p<0.01; 2.506 vs. 1.210, p<0.01). Distinctive positive staining in bile ducts were seen in CC, HB tumor and non-tumor liver tissues for FGFR2 and CEBPB. Percentages of CEBPB-immuno-positive or FGFR2-immuno-positive bile duct cells in CC and HB-tumor liver were higher than that in HB non-tumor liver. INTERPRETATION: The study identified dysregulated genes related to cancer pathways in CC patients suggesting cancer risk. The findings suggest that the elevated expression of FGFR2 and CEBPB in liver may contribute to cancer development in CC patients.

Does the Choice of Suture Materials Affect the Vas Deferens after Hernia Ring Closure in Inguinal Hernia Surgery: An Experimental Study in Rats.

INTRODUCTION: Laparoscopic inguinal hernia repair is a commonly performed procedure in children. Currently, monofilament polypropylene and braided silk are the two most frequently used materials. Studies have suggested more tissue inflammatory reactions with the use of multifilament non-absorbable sutures. However, little is known about the effects of suture materials on adjacent vas deferens. The aim of this experiment was to compare the effect of non-absorbable monofilament and multifilament sutures on vas deferens in laparoscopic hernia repair. METHODS: All animal operations were performed by a single surgeon under aseptic conditions and anaesthesia. Ten male Sprague Dawley rats were divided into two groups. In Group I, "hernia repair" was performed using 5.0 Silk. In Group II, polypropylene sutures (Prolene®; Ethicon, Somerville, N.J., USA) were used. All animals also received sham operations in the left groin as a control. After 14 days, the animals were euthanised and a segment of vas deferens just adjacent to the suture was excised for histological review by an experienced pathologist who was blind to the treatment groups of the respective specimens. RESULTS: The body sizes of the rats in each group were comparable. Group I had significantly smaller vas deferens than Group II (diameter: 0.2 vs. 0.6 ± 0.2, p = 0.005). Silk sutures appeared to cause more tissue adhesion than Prolene® sutures, as graded by blind assessors (adhesion grade: 2.8 ± 1.3 vs. 1.8 ± 0.8, p = 0.1), although this did not reach statistical significance. There was no significant difference in the histological fibrosis score and inflammation score. CONCLUSION: The only effect of non-absorbable sutures on vas deferens in this rat model was the reduced cross-sectional area of vas deferens and increased tissue adhesion when using silk sutures. However, there was no significant histological difference in inflammation or fibrosis caused by either material.

Primary anastomosis is the preferred surgical approach for proximal intestinal atresia: a retrospective 20-year analysis.

PURPOSE: We aimed to compare the outcomes of primary anastomosis (PA) and enterostomy as treatments for intestinal atresia in neonates to identify the factors influencing the choice of modality. METHODS: We conducted a retrospective single-centre analysis of all neonates with intestinal atresia between 2000 and 2020 and measured the clinical outcomes. We performed logistic regression to identify factors that influenced the choice of surgical approach. RESULTS: Of 62 intestinal atresia neonates, 71% received PA. There were no significant differences in gestation, gender, age at operation, birth weight, or body weight at operation between the PA and enterostomy groups. PA reoperation was not required for 78% of patients, and the PA group had shorter hospital stays. Complications, operative time, duration on parenteral nutrition, time to full enteral feeding were comparable in both groups. Upon multivariate regression analysis, surgeons favoured PA in proximal atresia [Odds ratio (OR) 38.5, 95% Confidence Interval (CI) 2.558-579] while enterostomy in smaller body size [OR 2.75, CI 0.538-14.02] and lower Apgar score [OR 1.1, CI 0.07-17.8]. Subgroup analysis in these patient groups demonstrated comparable outcomes with both surgical approaches. CONCLUSION: Both surgical approaches achieved comparable outcomes, but PA was associated with short hospital stays and the avoidance of stoma-related complications, and reoperation was generally not required. This surgical approach was suitable for patients with proximal atresia, but enterostomy remained a sensible choice for patients with smaller body sizes and lower Apgar scores.

Enhanced recovery after surgery in pediatric urology: Current evidence and future practice.

PURPOSE: To offer an up-to-date appraisal of the current status of enhanced recovery after surgery (ERAS) protocols in pediatric urology and to provide a guide for the clinical urologist. MATERIALS AND METHODS: We performed a comprehensive literature search and scoping review on ERAS protocols in pediatric urology using Pubmed (from 1946), Cochrane library, and MEDLINE to December 2021 with the terms ''enhanced recovery'', ''protocolised care'', ''post-operative protocol", ''fast-track surgery'' and ''pediatric urology". Studies were excluded if they did not include perioperative intervention related to urological procedures, no full-text available and in non-English language. RESULTS: To date, eight clinical studies (involving 1153 patients) have been published on ERAS protocols in pediatric urology. The patients involved ranged from neonates to adolescents, and the urological procedures included bladder augmentation, the Mitrofanoff procedure, laparoscopic pyeloplasty, laparoscopic nephrectomy, hypospadias repair, etc. Multidisciplinary components such as surgical and anesthetic considerations have been employed in ERAS protocols. The length of hospital stay was significantly lower in the ERAS groups with earlier enteral feeding resumption and return of bowel function in pediatric urology patients. The implementation of ERAS protocols does not result in higher complication and readmission rates; instead, some studies have even demonstrated a significant reduction in complication occurrence. CONCLUSION: ERAS is novel to pediatric urology with a limited scale of published data in the literature. Initial clinical studies revealed that ERAS appears to be efficacious in the field of pediatric urology. Further prospective studies formulating a standardized multimodal protocol are encouraged to better understand key components of ERAS and incorporate ERAS into clinical practice to optimize surgical outcomes for pediatric urology procedures.

Outcome and learning curve for laparoscopic intra-corporeal inguinal hernia repair in children.

BACKGROUND: Laparoscopic inguinal hernia repair is one of the procedures most commonly performed by paediatric surgeons. Current research on the learning curve for laparoscopic hernia repair in children is scarce. This study aims to evaluate the clinical outcome and learning curve of laparoscopic intra-corporeal inguinal hernia repair in children. METHODS: A retrospective single-centre analysis of all paediatric patients who underwent laparoscopic intra-corporeal inguinal hernia repair between 2010 and 2019 was performed. The clinical outcomes were analysed. The data on the achievement of the learning curve by surgical trainees were evaluated with the CUSUM technique, focusing on operative time. RESULTS: There were 719 patients with laparoscopic intra-corporeal inguinal hernia repair (comprising 1051 sides) performed during the study period. The overall ipsilateral recurrence rate was 1.8% without other complications detected. CUSUM analysis showed that there were 3 phases of training, for which the trainees underwent initial learning phase (Phase 1) for the first 7 cases. After mastering of the skills and extrapolating the skills to male patients with smaller body size (Phase 2), they then achieved performance comparable to that of the senior surgeons after 18 procedures (Phase 3). CONCLUSIONS: 18 procedures seem to be the number required to reach the learning curve plateau in terms of operative time by surgical trainees. The clinical outcomes show that laparoscopic intra-corporeal inguinal hernia repair is a safe and transferrable technique, even in the hands of trainees, with adequate supervision and careful case selection. It also provides skill acquisition for minimally invasive surgery.

Plasma amyloid-beta levels correlated with impaired hepatic functions: An adjuvant biomarker for the diagnosis of biliary atresia.

Background: Biliary atresia (BA) is an infantile fibro-obstructive cholestatic disease with poor prognosis. An early diagnosis and timely Kasai portoenterostomy (KPE) improve clinical outcomes. Aggregation of amyloid-beta (Aß) around hepatic bile ducts has been discovered as a factor for BA pathogenesis, yet whether plasma Aß levels correlate with hepatic dysfunctions and could be a biomarker for BA remains unknown. Method: Plasma samples of 11 BA and 24 controls were collected for liver function test, Aß40 and Aß42 measurement by enzyme-linked immunosorbent assay (ELISA). Pearson's chi-squared test or Mann-Whitney U test was performed to assess differences between groups. Correlation between Aß42/Aß40 and liver function parameters was performed using Pearson analysis. The area under the receiver-operative characteristic (ROC) curve (area under curve; AUC) was measured to evaluate the diagnostic power of Aß42/Aß40 for BA. Diagnostic enhancement was further evaluated by binary regression ROC analysis of Aß42/Aß40 combined with other hepatic function parameters. Results: Plasma Aß42/Aß40 was elevated in BA patients. Aß42 displayed a weak positive correlation with γ-glutamyl transpeptidase (GGT) (Pearson's correlation = 0.349), while there was no correlation for Aß40 with hepatic functions. Aß42/Aß40 was moderately correlated with GGT, total bile acid (TBA), direct bilirubin (DBIL) (Pearson's correlation = 0.533, 0.475, 0.480), and weakly correlated with total bilirubin (TBIL) (Pearson's correlation = 0.337). Aß42/Aß40 showed an acceptable predictive power for cholestasis [AUC = 0.746 (95% CI: 0.552-0.941), p < 0.05]. Diagnostic powers of Aß42/Aß40 together with hepatic function parameters for cholestasis were markedly improved compared to any indicator alone. Neither Aß42/Aß40 nor hepatic function parameters displayed sufficient power in discriminating BA from choledochal cysts (CC); however, combinations of Aß42/Aß40 + GGT along with any other hepatic function parameters could differentiate BA from CC-cholestasis (AUC = 1.000, p < 0.05) with a cut-off value as 0.02371, -0.28387, -0.34583, 0.06224, 0.01040, 0.06808, and 0.05898, respectively. Conclusion: Aß42/Aß40 is a good indicator for cholestasis, but alone is insufficient for a distinction of BA from non-BA. However, Aß42/Aß40 combined with GGT and one other hepatic function parameter displayed a high predictive power as a screening test for jaundiced neonates who are more likely to be BA, enabling them to early intraoperative cholangiography for BA confirmation and KPE to improve surgical outcomes. However, a multi-centers validation is needed before introduction into daily clinical practice.

Coronaviruses exploit a host cysteine-aspartic protease for replication.

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs. 1,2) (SARS-CoV-2), Middle East respiratory syndrome coronavirus3 (MERS-CoV) and SARS-CoV-1 (ref. 4), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture5-7 and in patient tissues8-10, suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication.

Regenerative medicine: postnatal approaches.

Paper 2 of the paediatric regenerative medicine Series focuses on recent advances in postnatal approaches. New gene, cell, and niche-based technologies and their combinations allow structural and functional reconstitution and simulation of complex postnatal cell, tissue, and organ hierarchies. Organoid and tissue engineering advances provide human disease models and novel treatments for both rare paediatric diseases and common diseases affecting all ages, such as COVID-19. Preclinical studies for gastrointestinal disorders are directed towards oesophageal replacement, short bowel syndrome, enteric neuropathy, biliary atresia, and chronic end-stage liver failure. For respiratory diseases, beside the first human tracheal replacement, more complex tissue engineering represents a promising solution to generate transplantable lungs. Genitourinary tissue replacement and expansion usually involve application of biocompatible scaffolds seeded with patient-derived cells. Gene and cell therapy approaches seem appropriate for rare paediatric diseases of the musculoskeletal system such as spinal muscular dystrophy, whereas congenital diseases of complex organs, such as the heart, continue to challenge new frontiers of regenerative medicine.

Regenerative medicine: prenatal approaches.

This two-paper Series focuses on recent advances and applications of regenerative medicine that could benefit paediatric patients. Innovations in genomic, stem-cell, and tissue-based technologies have created progress in disease modelling and new therapies for congenital and incurable paediatric diseases. Prenatal approaches present unique opportunities associated with substantial biotechnical, medical, and ethical obstacles. Maternal plasma fetal DNA analysis is increasingly adopted as a noninvasive prenatal screening or diagnostic test for chromosomal and monogenic disorders. The molecular basis for cell-free DNA detection stimulated the development of circulating tumour DNA testing for adult cancers. In-utero stem-cell, gene, gene-modified cell (and to a lesser extent, tissue-based) therapies have shown early clinical promise in a wide range of paediatric disorders. Fetal cells for postnatal treatment and artificial placenta for ex-utero fetal therapies are new frontiers in this exciting field.