Outcomes After Transfer of Pediatric Trauma Patients: Does Everyone Need to Visit the Trauma Bay?

INTRODUCTION: Critically injured children and teens often present to adult trauma centers or nontrauma facilities prior to transfer to a pediatric trauma center. For pediatric patients wanting transfer to the intensive care unit (ICU), there is little data to guide which can be safely transferred directly to the unit, and which should be evaluated first in the trauma bay. METHODS: We used our institutional trauma registry to evaluate transferred trauma patients over a three year period. We compared time to imaging, time to operating room, and overall mortality between the group evaluated first in the emergency room and those transferred directly to the ICU. RESULTS: When adjusted for other variables, there was no increased mortality in those transferred directly to the ICU. While there was a higher nonadjusted mortality in those transferred to the ICU (13% versus 3.7%), these nonsurvivors had a lower GCS (3 versus 13), higher Pediatric Risk of Mortality scores, and a high rate of severe head trauma. There was no significant delay in ordered imaging or procedures. CONCLUSIONS: In patients, who have been assessed at another institution prior to transfer to the pediatric ICU, transfer directly to the ICU, bypassing the emergency department, does not delay interventions and does not appear to worsen outcomes.

Obesity Protects Against Operation in Pediatric Penetrating Trauma to the Torso.

BACKGROUND: Studies in the adult population are conflicting regarding whether obesity is protective in penetrating trauma. In the pediatric population, data on obesity and penetrating trauma are limited. We sought to determine if there is a different rate of operation or of survival in pediatric and adolescent patients with obesity. METHODS: We queried the National Trauma Data Bank research data set from 2013 to 2016 for all patients aged 2-18 who sustained traumatic penetrating injuries to the thorax and abdomen. The cohort was divided into body mass index percentiles for gender and age using Center for Disease Control definitions. Outcomes included overall survival, whether or not an operative procedure was performed, and hospital and intensive care unit (ICU) length of stay. RESULTS: We analyzed 9611 patients with penetrating trauma, of which 4285 had an operative intervention. When adjusted for other variables (age, gender, race, ICU length of stay, hospital length of stay, and Injury Severity Score), children of every body mass index percentile had similar survival. Healthy weight patients were more likely to get an operation than patients in the obese category. Length of hospital stay was similar between groups, but the ICU length of stay was longer in the overweight and obese groups compared with healthy weight and underweight groups. CONCLUSIONS: Children and adolescents with obesity are less likely to undergo operation after penetrating thoracoabdominal trauma. Further study is needed to determine the reason for this difference.

Short-term and long-term human or mouse organoid units generate tissue-engineered small intestine without added signalling molecules.

NEW FINDINGS: What is the central question of this study? Tissue-engineered small intestine was previously generated in vivo by immediate implantation of organoid units derived from both mouse and human donor intestine. Although immediate transplantation of organoid units into patients shows promise as a potential future therapy, some critically ill patients might require delayed transplantation. What is the main finding and its importance? Unlike enteroids, which consist of isolated intestinal crypts, short- and long-term cultured organoid units are composed of epithelial and mesenchymal cells derived from mouse or human intestine. Organoid units do not require added signalling molecules and can generate tissue-engineered intestine in vivo. ABSTRACT: Mouse and human postnatal and fetal organoid units (OUs) maintained in either short-term culture (2 weeks) or long-term culture (from 4 weeks up to 3 months) without adding exogenous growth factors were implanted in immunocompromised mice to form tissue-engineered small intestine (TESI) in vivo. Intestinal epithelial stem and neuronal progenitor cells were maintained in long-term OU cultures from both humans and mice without exogenous growth factors, and these cultures were successfully used to form TESI. This was enhanced with OUs derived from human fetal tissues. Organoid unit culture is different from enteroid culture, which is limited to epithelial cell growth and requires supplementation with R-Spondin, noggin and epidermal growth factor. Organoid units contain multiple cell types, including epithelial, mesenchymal and enteric nervous system cells. Short- and long-term cultured OUs derived from mouse and human intestine develop into TESI in vivo, which contains key components of the small intestine similar to native intestine.

On the utility of a compartmental population kinetics model of intestinal epithelial stem cell proliferation and differentiation.

BACKGROUND: The small intestinal epithelium is a dynamic system with specialized cell types. The various cell populations of this tissue are continually renewed and replenished from stem cells that reside in the small intestinal crypt. The cell types and their locations in the crypt and villus are well known, but the details of the kinetics of stem cell division, and precursor cell proliferation and differentiation into mature enterocytes and secretory cells are still being studied. These proliferation and differentiation events have been extensively modeled with a variety of computational approaches in the past. METHODS: A compartmental population kinetics model, incorporating experimentally measured proliferation rates for various intestinal epithelial cell types, is implemented for a previously reported scheme for the intestinal cell dynamics. A sensitivity analysis is performed to determine the effect that varying the model parameters has upon the model outputs, the steady-state cell populations. RESULTS: The model is unable to reproduce the experimentally known timescale of renewal of the intestinal epithelium if literature values for the proliferation rates of stem cells and transit amplifying cells are employed. Unphysically large rates of proliferation result when these parameters are allowed to vary to reproduce this timescale and the steady-state populations of terminally differentiated intestinal epithelial cells. Sensitivity analysis reveals that the strongest contributor to the steady-state populations is the transit amplifying cell proliferation rate when literature values are used, but that the differentiation rate of transit amplifying cells to secretory progenitor cells dominates when all parameters are allowed to vary. CONCLUSIONS: A compartmental population kinetics model of proliferation and differentiation of cells of the intestinal epithelium can provide a simplifying means of understanding a complicated multistep process. However, when literature values for proliferation rates of the crypt based columnar and transit amplifying cell populations are employed in the model, it cannot reproduce the experimentally known timescale of intestinal epithelial renewal. Nevertheless, it remains a valuable conceptual tool, and its sensitivity analysis provides important clues for which events in the process are the most important in controlling the steady-state populations of specialized intestinal epithelial cells.

Fgf10 overexpression enhances the formation of tissue-engineered small intestine.

Short bowel syndrome (SBS) is a morbid and mortal condition characterized in most patients by insufficient intestinal surface area. Current management strategies are inadequate, but tissue-engineered small intestine (TESI) offers a potential therapy. A barrier to translation of TESI is the generation of scalable mucosal surface area to significantly increase nutritional absorption. Fibroblast growth factor 10 (Fgf10) is a critical growth factor essential for the development of the gastrointestinal tract. We hypothesized that overexpression of Fgf10 would improve the generation of TESI. Organoid units, the multicellular donor tissue that forms TESI, were derived from Rosa26(rtTA/+), tet(o)Fgf10/(-) or Fgf10(Mlc-nlacZ-v24) (hereafter called Fgf10(lacZ)) mice. These were implanted into the omentum of NOD/SCID γ-chain-deficient mice and induced with doxycycline in the case of tet(o)Fgf10/(-). Resulting TESI were explanted at 4 weeks and studied by histology, quantitative RT-PCR and immunofluorescence. Four weeks after implantation, Fgf10 overexpressing TESI was larger and weighed more than the control tissues. Within the mucosa, the villus height was significantly longer and crypts contained a greater percentage of proliferating epithelial cells. A fully differentiated intestinal epithelium with enterocytes, goblet cells, enteroendocrine cells and Paneth cells was identified in the Fgf10-overexpressing TESI, comparable to native small intestine. ß-Galactosidase expression was found in both the epithelium and the mesenchyme of the TESI derived from the Fgf10(LacZ) duodenum. However, this was not the case with TESI generated from jejunum and ileum. We conclude that Fgf10 enhances the formation of TESI.

Human and mouse tissue-engineered small intestine both demonstrate digestive and absorptive function.

Short bowel syndrome (SBS) is a devastating condition in which insufficient small intestinal surface area results in malnutrition and dependence on intravenous parenteral nutrition. There is an increasing incidence of SBS, particularly in premature babies and newborns with congenital intestinal anomalies. Tissue-engineered small intestine (TESI) offers a therapeutic alternative to the current standard treatment, intestinal transplantation, and has the potential to solve its biggest challenges, namely donor shortage and life-long immunosuppression. We have previously demonstrated that TESI can be generated from mouse and human small intestine and histologically replicates key components of native intestine. We hypothesized that TESI also recapitulates native small intestine function. Organoid units were generated from mouse or human donor intestine and implanted into genetically identical or immunodeficient host mice. After 4 wk, TESI was harvested and either fixed and paraffin embedded or immediately subjected to assays to illustrate function. We demonstrated that both mouse and human tissue-engineered small intestine grew into an appropriately polarized sphere of intact epithelium facing a lumen, contiguous with supporting mesenchyme, muscle, and stem/progenitor cells. The epithelium demonstrated major ultrastructural components, including tight junctions and microvilli, transporters, and functional brush-border and digestive enzymes. This study demonstrates that tissue-engineered small intestine possesses a well-differentiated epithelium with intact ion transporters/channels, functional brush-border enzymes, and similar ultrastructural components to native tissue, including progenitor cells, whether derived from mouse or human cells.

Surgical malpractice in California: res judicata.

Medical negligence claims are of increasing concern to surgeons. Although noneconomic damage awards in California are limited by the Medical Injury Compensation Reform Act (MICRA) law to $250,000, the total amount of such settlements can increase significantly based on claims for economic damages. We reviewed negligence litigation involving California surgeons to determine outcomes and monetary awards through retrospective review of surgical malpractice cases published in a legal journal. This review was limited to actions involving general surgeons. Such litigation was voluntarily reported by either defense's or plaintiff's counsel at the conclusion of the litigation. Data reviewed included alleged damages incurred by the plaintiff; plaintiff's pretrial settlement demand, plaintiff or defense verdict, use of alternate means of resolution such as arbitration or mediation, and total monetary award to the plaintiff. A total of 69 cases were reported over a 20-month period: 32 (46%) were plaintiffs' verdicts, whereas 37 (54%) were in favor of the surgeon. Only 10 (31%) of the plaintiff verdicts were by jury trial, whereas the rest were settled by pretrial agreement, mediation, or arbitration. Of cases settled by alternate dispute resolution, the median settlement was $820,000 (n = 22) compared with a median jury trial award of $300,000 (n = 10).

Delayed family reunification of pediatric disaster survivors increases mortality and inpatient hospital costs: a simulation study.

BACKGROUND: Disasters occur randomly and can severely tax the health care delivery system of affected and surrounding regions. A significant proportion of disaster survivors are children, who have unique medical, psychosocial, and logistical needs after a mass casualty event. Children are often transported to specialty centers after disasters for a higher level of pediatric care, but this can also lead to separation of these survivors from their families. In a recent theoretical article, we showed that the availability of a pediatric trauma center after a mass casualty event would decrease the time needed to definitively treat the pediatric survivor cohort and decrease pediatric mortality. However, we also found that if the pediatric center was too slow in admitting and discharging patients, these benefits were at risk of being lost as children became "trapped" in the slow center. We hypothesized that this effect could result in further increased mortality and greater costs. METHODS: Here, we expand on these ideas to test this hypothesis via mathematical simulation. We examine how a delay in discharge of part of the pediatric cohort is predicted to affect mortality and the cost of inpatient care in the setting of our model. RESULTS: We find that mortality would increase slightly (from 14.2%-16.1%), and the cost of inpatient care increases dramatically (by a factor of 21) if children are discharged at rates consistent with reported delays to reunification after a disaster from the literature. CONCLUSIONS: Our results argue for the ongoing improvement of identification technology and logistics for rapid reunification of pediatric survivors with their families after mass casualty events.

A "living bioreactor" for the production of tissue-engineered small intestine.

Here, we describe the use of a mouse model as a living bioreactor for the generation of tissue-engineered small intestine. Small intestine is harvested from donor mice with subsequent isolation of organoid units (a cluster of mesenchymal and epithelial cells). Some of these organoid units contain pluripotent stem cells with a preserved relationship with the mesenchymal stem cell niche. A preparation of organoid units is seeded onto a biodegradable scaffold and implanted intraperitoneally within the omentum of the host animal. The cells are nourished initially via imbibition until neovascularization occurs. This technique allows the growth of fully differentiated epithelium (composed of Paneth cells, goblet cells, enterocytes and enteroendocrine cells), muscle, nerve, and blood vessels of donor origin. Variations of this technique have been used to generate tissue-engineered stomach, large intestine, and esophagus. The variations include harvest technique, length of digestion, and harvest times.

Human tissue-engineered small intestine forms from postnatal progenitor cells.

PURPOSE: Tissue-engineered small intestine (TESI) represents a potential cure for short bowel syndrome (SBS). We previously reported full-thickness intestine formation using an organoid units-on-scaffold approach in rodent and swine models. Transplanted intestinal xenografts have been documented to survive from human fetal tissue but not from postnatal tissue. We now present the first report of human TESI from postnatal tissue. METHODS: Organoid units (OU) were prepared from human small bowel resection specimens, loaded onto biodegradable scaffolds and implanted into NOD/SCID gamma chain-deficient mice. After 4 weeks, TESI was harvested and immunostained for ß2-microglobulin to identify human tissue, villin for enterocytes, lysozyme for Paneth cells, chromogranin-A for enteroendocrine cells, mucin-2 for goblet cells, smooth muscle actin and desmin to demonstrate muscularis, and S-100 for nerves. RESULTS: All TESI was of human origin. Immunofluorescence staining of human TESI reveals the presence of all four differentiated cell types of mature human small intestine, in addition to the muscularis and the supporting intestinal subepithelial myofibroblasts. Nerve tissue is also present. CONCLUSIONS: Our technique demonstrates survival, growth, and differentiation of postnatally derived human small intestinal OU into full thickness TESI in murine hosts. This regenerative medicine strategy may eventually assist in the treatment of SBS.

Tissue engineering of the intestine in a murine model.

Tissue-engineered small intestine (TESI) has successfully been used to rescue Lewis rats after massive small bowel resection, resulting in return to preoperative weights within 40 days.(1) In humans, massive small bowel resection can result in short bowel syndrome, a functional malabsorptive state that confers significant morbidity, mortality, and healthcare costs including parenteral nutrition dependence, liver failure and cirrhosis, and the need for multivisceral organ transplantation.(2) In this paper, we describe and document our protocol for creating tissue-engineered intestine in a mouse model with a multicellular organoid units-on-scaffold approach. Organoid units are multicellular aggregates derived from the intestine that contain both mucosal and mesenchymal elements,(3) the relationship between which preserves the intestinal stem cell niche.(4) In ongoing and future research, the transition of our technique into the mouse will allow for investigation of the processes involved during TESI formation by utilizing the transgenic tools available in this species.(5)The availability of immunocompromised mouse strains will also permit us to apply the technique to human intestinal tissue and optimize the formation of human TESI as a mouse xenograft before its transition into humans. Our method employs good manufacturing practice (GMP) reagents and materials that have already been approved for use in human patients, and therefore offers a significant advantage over approaches that rely upon decellularized animal tissues. The ultimate goal of this method is its translation to humans as a regenerative medicine therapeutic strategy for short bowel syndrome.

Human tissue-engineered colon forms from postnatal progenitor cells: an in vivo murine model.

AIM: Loss of colon reservoir function after colectomy can adversely affect patient outcomes. In previous work, human fetal intestinal cells developed epithelium without mesenchyme following implantation in mice. However, for humans, postnatal tissue would be the preferred donor source. We generated tissue-engineered colon (TEC) from postnatal human organoid units. MATERIALS & METHODS: Organoid units were prepared from human colon waste specimens, loaded onto biodegradable scaffolds and implanted into immunocompromised mice. After 4 weeks, human TEC was harvested. Immunofluorescence staining confirmed human origin, identified differentiated epithelial cell types and verified the presence of supporting mesenchyme. RESULTS: Human TEC demonstrated a simple columnar epithelium. Immunofluorescence staining demonstrated human origin and the three differentiated cell types of mature colon epithelium. Key mesenchymal components (smooth muscle, intestinal subepithelial myofibroblasts and ganglion cells) were seen. CONCLUSION: Colon can form from human progenitor cells on a scaffold in a mouse host. This proof-of-concept experiment is an important step in transitioning TEC to human therapy.

Calcified gallstone in a 3 year-old boy: a case report.

BACKGROUND: Gallstones are relatively rare in children. At-risk populations include patients suffering from hemolysis syndromes. Regardless of etiology, these patients usually will present with postprandial abdominal pain, and ultrasonography is the mainstay of diagnosis. However, some gallstones are radiopaque and can be visualized on plain abdominal radiography. CASE PRESENTATION: We present the uncommon but classic plain x-ray finding of a calcified gallstone in a 3 year-old Hispanic boy. He was treated with elective laparoscopic cholecystectomy. CONCLUSIONS: Cholelithiasis is rare in children, and calcified stones that will appear on plain abdominal x-rays are even rarer. If symptomatic, cholecystectomy by a pediatric surgeon is the treatment of choice. We discuss some of the recent developments in treatment of this condition in this patient population.

Giant cystic meconium peritonitis presenting in a neonate with classic radiographic eggshell calcifications and treated with an elective surgical approach: a case report.

INTRODUCTION: Giant cystic meconium peritonitis is relatively rare. Patients often present with nonspecific physical findings such as distension and emesis. Plain abdominal films remain invaluable for identifying the characteristic calcifications seen with a meconium pseudocyst, and large eggshell calcifications are pathognomonic for the giant cystic subtype. CASE PRESENTATION: We present classic plain X-ray findings and an intraoperative image of a premature low birth weight two-day-old Hispanic male baby treated for giant cystic meconium peritonitis with a staged procedure involving peritoneal drainage, ostomy creation and closure. CONCLUSION: Pediatric surgeons have a range of potential therapeutic approaches for giant cystic meconium peritonitis. A delay of definitive surgical management in the setting of massive abdominal soiling is a safe and acceptable strategy if adequate temporizing drainage is performed in the early perinatal period.

Can a pediatric trauma center improve the response to a mass casualty incident?

UNLABELLED: Recent events including the 2001 terrorist attacks on New York; Hurricane Katrina; the 2010 Haitian and Chilean earthquakes; and the 2011 earthquake, tsunami, and nuclear disaster in Japan have reminded disaster planners and responders of the tremendous scale of mass casualty disasters and their resulting human devastation. Although adult disaster medicine is a well-developed field with roots in wartime medicine, we are increasingly recognizing that children may comprise up to 50% of disaster victims, and response mechanisms are often designed without adequate preparation for the number of pediatric victims that can result. In this short educational review, we explore the differences between the pediatric and adult disaster and trauma populations, the requirements for designation of a site as a pediatric trauma center (PTC), and the magnitude of the problem of pediatric disaster patients as described in the literature, specifically as it pertains to the availability and use of designated PTCs as opposed to trauma centers in general. We also review our own experience in planning and simulating pediatric mass casualty events and suggest strategies for preparedness when there is no PTC available. We aim to demonstrate from this brief survey that the availability of a designated PTC in the setting of a mass casualty disaster event is likely to significantly improve the outcome for the pediatric demographic of the affected population. We conclude that the relative scarcity of disaster data specific to children limits epidemiologic study of the pediatric disaster population and offer suggestions for strategies for future study of our hypothesis. LEVEL OF EVIDENCE: Systematic review, level III.

Steady-state and time-dependent thermodynamic modeling of the effect of intravenous infusion of warm and cold fluids.

BACKGROUND: Hypothermia results in vital sign lability, coagulopathy, wound infections, and other sequelae. Normothermia can be restored by several modalities, including passive blanket heating, warm forced-air devices, and active fluid warming (AFW). In AFW, intravenously administered fluids are heated to 40 to 45 °C to minimize net thermal losses and to raise body temperature. Clinical studies have demonstrated the efficacy of AFW as part of a strategy encompassing several methods, but the isolated contribution of AFW to warming has not been theoretically examined in detail. METHODS: A calorimetric model is derived to determine the functional dependence of warming on patient weight, hypothermia severity, infusion temperature, and volume infused. A second heat transfer model is derived to describe the time-dependent temperature changes of the periphery and core after warmed-fluid infusion. RESULTS: There is an inverse linear relationship between the patient's initial temperature and the amount of warming achieved with a given volume. In contrast, as the temperature of the infusion approaches the desired final temperature, the volume required for a fixed temperature change increases nonlinearly. For weight-based boluses, the temperature change scales appropriately with patient mass. Infusion of 2 L of room-temperature crystalloid results in a decrease in body temperature of approximately one-third degree Celsius in the average normothermic adult. For the heat transfer model, previously reported rates of temperature drop and recovery after the intravenous infusion of cold fluids are qualitatively reproduced with a blood mixing time of approximately 15 minutes. CONCLUSION: Our calculations reveal that AFW has a larger measurable beneficial effect for patients with more severe hypothermia, but true rewarming of the patient with AFW alone would require prohibitively large fluid volumes (more than 10 L of 40 °C fluid) or dangerously hot fluid (20 mL/kg of 80 °C fluid for a 1 °C increase). The major beneficial effect of AFW is the prevention of further net heat loss.

Solid pseudopapillary tumor of the pancreas: a single-institution 20-year series of pediatric patients.

PURPOSE: Solid pseudopapillary tumor (SPT) of the pancreas is a rare neoplasm. The objective of this study was to review our institution's experience and provide an update on current management in the pediatric population. METHODS: Our pathology database identified all patients with SPT for a 20-year period (1991-2011). Demographics, clinical characteristics, operative details, pathology, and outcomes data were retrospectively reviewed. RESULTS: Eleven patients with SPT were identified. Most were female and Hispanic. Median age at resection was 14 years (9-17 years). Most patients presented with abdominal pain. Diagnostic imaging was most commonly an ultrasound or computed tomography. All tumors were resected en bloc. Median greatest tumor diameter was 5 cm (3.5-12 cm). Median length of stay was 8 days (5-19 days). Complications included pancreatic leak, chyle leak, delayed gastric emptying, fat malabsorption, and incisional keloid. Recurrence developed after 2.5 years in 1 patient with positive surgical margins. There were no metastases or deaths. Median follow-up was 1.4 years (0.6-5.9 years). CONCLUSION: This pediatric series of SPT from a single institution corroborates previous reports in the literature. In our experience, SPT behaves like a low-grade malignancy and has an excellent prognosis. Surgical resection is dictated by tumor location and remains the treatment of choice.

Sigmoid perforation and bucket-handle tear of the mesocolon after bicycle handlebar injury: a case report and review of the literature.

We describe an unusual case of sigmoid colon perforation secondary to a bicycle handlebar injury. Because the patient presented 2 days after the initial injury, we suspected that the colon perforation was not the immediate result of the bicycle accident but, rather, was secondary to devascularization. At operation, we found a bucket-handle tear of the colonic mesentery, which was the patient's primary injury and cause of the perforated colon.

Availability of a pediatric trauma center in a disaster surge decreases triage time of the pediatric surge population: a population kinetics model.

BACKGROUND: The concept of disaster surge has arisen in recent years to describe the phenomenon of severely increased demands on healthcare systems resulting from catastrophic mass casualty events (MCEs) such as natural disasters and terrorist attacks. The major challenge in dealing with a disaster surge is the efficient triage and utilization of the healthcare resources appropriate to the magnitude and character of the affected population in terms of its demographics and the types of injuries that have been sustained. RESULTS: In this paper a deterministic population kinetics model is used to predict the effect of the availability of a pediatric trauma center (PTC) upon the response to an arbitrary disaster surge as a function of the rates of pediatric patients' admission to adult and pediatric centers and the corresponding discharge rates of these centers. We find that adding a hypothetical pediatric trauma center to the response documented in an historical example (the Israeli Defense Forces field hospital that responded to the Haiti earthquake of 2010) would have allowed for a significant increase in the overall rate of admission of the pediatric surge cohort. This would have reduced the time to treatment in this example by approximately half. The time needed to completely treat all children affected by the disaster would have decreased by slightly more than a third, with the caveat that the PTC would have to have been approximately as fast as the adult center in discharging its patients. Lastly, if disaster death rates from other events reported in the literature are included in the model, availability of a PTC would result in a relative mortality risk reduction of 37%. CONCLUSIONS: Our model provides a mathematical justification for aggressive inclusion of PTCs in planning for disasters by public health agencies.

A multicellular approach forms a significant amount of tissue-engineered small intestine in the mouse.

Tissue-engineered small intestine (TESI) has successfully been used to rescue Lewis rats after massive small bowel resection. In this study, we transitioned the technique to a mouse model, allowing investigation of the processes involved during TESI formation through the transgenic tools available in this species. This is a necessary step toward applying the technique to human therapy. Multicellular organoid units were derived from small intestines of transgenic mice and transplanted within the abdomen on biodegradable polymers. Immunofluorescence staining was used to characterize the cellular processes during TESI formation. We demonstrate the preservation of Lgr5- and DcamKl1-positive cells, two putative intestinal stem cell populations, in proximity to their niche mesenchymal cells, the intestinal subepithelial myofibroblasts (ISEMFs), at the time of implantation. Maintenance of the relationship between ISEMF and crypt epithelium is observed during the growth of TESI. The engineered small intestine has an epithelium containing a differentiated epithelium next to an innervated muscularis. Lineage tracing demonstrates that all the essential components, including epithelium, muscularis, nerves, and some of the blood vessels, are of donor origin. This multicellular approach provides the necessary cell population to regenerate large amounts of intestinal tissue that could be used to treat short bowel syndrome.