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ASAIO J. 2024 Jun; 70(6): 527–534.
Published online 2024 Jan 3. doi:10.1097/MAT.0000000000002130
PMCID: PMC11139240
PMID: 38170278
Teja Karkhanis,* Achu G. Byju,* David L. Morales,† Farhan Zafar,† and Balakrishna Haridas
*
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
Pediatric patients who undergo surgery for long-segment congenital tracheal stenosis (LSCTS) have suboptimal outcomes and postsurgical complications. To address this, we propose a biosynthetic graft comprising (1) a porcine small intestinal submucosa extracellular matrix (SIS-ECM) patch for tracheal repair, and (2) a resorbable polymeric exostent for biomechanical support. The SIS-ECM patch was evaluated in vivo in an ovine trachea model over an 8 month period. Concurrently, the biosynthetic graft was evaluated in a benchtop lamb trachea model for biomechanical stability. In vivo results show that SIS-ECM performs better than bovine pericardium (control) by preventing granulation tissue/restenosis, restoring tracheal architecture, blood vessels, matrix components, pseudostratified columnar and stratified epithelium, ciliary structures, mucin production, and goblet cells. In vitro tests show that the biosynthetic graft can provide the desired axial and flexural stability, and biomechanical function approaching that of native trachea. These results encourage future studies to evaluate safety and efficacy, including biomechanics and collapse risk, biodegradation, and in vivo response enabling a stable long-term tracheal repair option for pediatric patients with LSCTS and other tracheal defects.
Keywords: congenital tracheal stenosis, biosynthetic graft, pediatric surgery
Congenital tracheal stenosis (CTS) or tracheal narrowing is a rare malformation affecting approximately 1 in 64,500 infants every year.1 Long-segment congenital tracheal stenosis (LSCTS) involves >30% of the trachea, and displays complete cartilage “O” rings and absent posterior muscular membranous wall, unlike the “C” shaped rings in a normal trachea (Figure (Figure1).1). Patients with LSCTS have high mortality rates (75%) if they do not receive surgical interventions.2 CTS is often accompanied by other congenital conditions, e.g., cardiovascular anomalies (in ~70% of patients), left pulmonary artery sling, ventricular septal defects, and other extra-thoracic defects.3,4 These comorbidities increase postsurgical mortality rates for CTS in patients (~53%), compared to 18% in patients without comorbidities.5
Figure 1.
Left: Anatomy of congenital tracheal stenosis (CTS) highlighting the complete tracheal rings. Right: Current surgical standards of care for CTS.
Slide tracheoplasty (ST) is the current “gold” standard for treating LSCTS (Figure (Figure11).1 The technique uses the intact cartilaginous rings to restore biomechanical stability while retaining the native airway epithelial structures. Although ST has improved survival rates (>80%), it is highly invasive due to extensive posterior tracheal mobilization producing a high-tension anastomosis driving complications including anastomotic dehiscence (3%), chylothorax (4%), hematopericardium, liver failure, renal failure, and pulmonary hypertension (2%).2 Approximately 20% of patients develop postoperative malacia and 40%–50% of patients require re-interventions after an ST.3
Patch tracheoplasty (PT) which employs a bioengineered patch is an alternative that allows for tension-free repair with an anterior surgical approach and no posterior mobilization or disruption of the blood supply (Figure (Figure11).6 However, PT has a higher incidence of restenosis/granulation tissue formation and tracheal collapse.7 PT patients require longer postsurgery intubation/ventilation times and stenting to treat restenosis,8 increasing respiratory complications, i.e., infection and pneumonia. Intraluminal stents to treat restenosis and tracheomalacia induce granulation, luminal scarring, erosion, and stent migration requiring re-interventions.9,10 Short length external airway splints used to treat tracheomalacia are not suitable for LSCTS procedures due to the reduced length.11
This article examines a new approach to improve patient outcomes by combining the advantages of slide and PT using a two-component biosynthetic graft:
Component #1: A patch material placed using the PT procedure, that remodels into functional tracheal luminal tissue, and
Component #2: An engineered resorbable polymeric external stent graft (exostent) sutured to the PT for biomechanical stability.
A reconstructed trachea using this graft could form viable mucosal and submucosal tissue while maintaining biomechanical stability during healing and remodeling. Over time, the external polymeric stent structure should slowly degrade and be replaced by a vascularized collagenous scar providing long-term support and accommodating growth. This anterior surgical approach using this graft minimizes tracheal mobilization. Additionally, the exostent can be trimmed and shaped during surgery to match the patient’s anatomy.
This article describes two proof-of-concept studies, with Study #1 assessing the ability of a biologic patch made from porcine Small Intestinal Submucosa-ExtraCellular Matrix (SIS-ECM) to form functional epithelium with minimal granulation in an ovine model of PT. Study #2 evaluates the in vitro biomechanics of an engineered resorbable exostent under radial force, axial tension, and bending deformation.
Methods
Study 1: Biologic Patch
The porcine SIS-ECM patch evaluated (CorMatrix Cardiovascular, Inc., Roswell, GA) contains four sheets of acellular, noncrosslinked porcine SIS, press-lyophilized into a patch.12 CorMatrix has been demonstrated in a variety of applications, e.g., lamb tricuspid valves (restoring structure/hemodynamics after 8 months), sheep right ventricle (restoring structure/electrical function after 8 months),13,14 and similar results in urinary tract and blood vessels.12,15
In this study, the SIS-ECM was used to repair a surgically created large tracheal defect in a growing ovine model. A bovine pericardial (BP) patch was used as control given its routine use in PT.4,6,16,17
Six (mixed breed and gender) sheep, approximately 4 months old (34 ± 2 kg), were included in the pilot study (Figure (Figure2),2), with four animals receiving SIS-ECM and two receiving BP repairs. Based on the promise shown by SIS-ECM in cardiothoracic tissue repair13,14 this imbalanced study design was chosen with due consideration to limit the overall number of animals. Three animals (two SIS-ECM and one BP) were euthanized at 4 months, and three at 8 months for histopathology. Serial bronchoscopies and MRI imaging were completed at 1.5, 4, and 8 months. These time points were selected based on prior experience with ovine models for the use of SIS-ECM in cardiothoracic tissue repair.13,14 All animals received humane care in compliance with National Institute of Health18 guidelines (Cincinnati Children’s Research Foundation #IACUC2021-0003).
Figure 2.
In vivo biologic patch evaluation study design. SIS-ECM: Small Intestinal Submucosa Extracellular Matrix; MRI: magnetic resonance imaging.
Sheep were intubated under general anesthesia using ketamine (5–15 mg/kg), midazolam (0.02–0.05 mg/kg) for induction, and isoflourane (1%–4%) for maintenance. Ceftiofur sodium (1–2.2 mg/kg) was given as antibiotic prophylaxis and buprenorphine (0.005–0.01mg/kg) for analgesia before incision. An endotracheal tube (ETT) was used for ventilation during repair of the trachea proximal to the cuff. A 2 cm × 1 cm tracheal defect was created in the cervical tracheal segment via an anterior incision. The defect was closed using the SIS-ECM or BP patch with running 5-0 Polydioxanone sutures. The ETT cuff was deflated, withdrawn proximally, and re-inflated to allow air leak testing of the repair. The edges of the patch were marked with nonferromagnetic surgical clips for identification during imaging and at explant.
Bronchoscopy
A 65 cm × 3.7 mm Storz Flexible bronchoscope capable of 140° deflection and 60× magnification was used to perform bronchoscopy at surgery and 1.5, 4, and 8 months postoperatively. Still images were captured at the proximal, middle, and distal end of the patch in all animals. Qualitative observations were recorded for gross luminal narrowing, change in patch surface, and abnormal growth.
Magnetic resonance imaging (MRI)
Each animal underwent an MRI under general anesthesia to evaluate patency and tracheal dimensions using a Philips Achieva 3T machine with a 32-element surface coil. Patch borders were identified by clips placed at the implant and expiratory breath holds were used for image acquisition as needed. Ellipticity (the condition of being elliptic) and tortuosity (linear distance/distance along the curve) of the trachea were measured and compared over time. Ellipticity ranges over (0–1) with a value of one assigned only if the measured shape is a pure ellipse. Ellipticity was averaged at four sections along the patch length. Tortuosity along the axis was evaluated for the trachea wherein a tortuosity of zero implies a straight line and the value increases proportional to the amount of curvature. These were measured as indicators of tracheal flattening and the resulting risk of tracheal collapse.
Tissue harvest, histology, and electron microscopy (EM)
Animals were euthanized using Fatal-Plus solution (phenobarbital 390 mg/ml, propylene-glycol 0.01 mg/ml, ethyl-alcohol 0.29 mg/ml, and benzyl-alcohol 0.2 mg/ml; Vortech Pharma, Dearborn, MI) 1 ml/10 lbs. The tracheal patch was collected en bloc with the surrounding native trachea. Hematoxylin and eosin, Trichrome, and periodic acid–Schiff (PAS) staining were performed on paraffin-embedded sections of proximal, middle, and distal patch areas along with the areas of native trachea. Presence of cilia, submucosal glands, cartilage, degree of epithelization, lymphocytic infiltration, and angiogenesis were assessed. Proliferating cells were detected using immunohistochemistry (rabbit-Ki-67 antibody, Ventana Medical Systems, Inc., Tucson, AZ) using the automated Ventana immunostainer per the manufacturer’s recommendations. Samples were also evaluated using standard electron microscopy protocols after serial dehydration to examine the cellular and morphological changes in the repair site.
Study 2: Resorbable Exostent
Design
The exostent (Figure (Figure3A)3A) is a semi-cylindrical structure made of poly ε-caprolactone (PCL) C-rings assembled on a Vicryl monofilament mesh (Ethicon Inc.). PCL is a well-known implant-grade resorbable polymer with a degradation time scale of 2–3 years. Before selecting PCL, multiple polymers, i.e., polyglycolic acid (PGA), poly lactic acid (PLA), and PLA-PCL copolymers were evaluated. Polymers were compared based on their degradation rates and experimentally measured bending properties of lamb tracheal rings as described in Karkhanis et al.19 The C-rings were engineered to match the native tracheal ring dimensions, and bending stiffness data for lamb tracheal cartilage.19 The Vicryl mesh serves as a carrier for the cartilage rings enabling handling, trimming, and suturing, and provides axial and bending flexibility to the reconstructed trachea in conjunction with the SIS-ECM patch after implantation.
Figure 3.
A: Exostent fabrication process: the poly ε-caprolactone (PCL) beams with pins are thermally staked to the Vicryl mesh and then shape set in the curved configuration. B: Trachea reconstructed with the exostent device.
Manufacturing
The PCL C-rings are initially injection molded as straight beams on a benchtop injection molding system (Galomb Model S-100) (Figure (Figure3A).3A). The beams have multiple equally spaced pin features that fit through the pores of the Vicryl mesh for final assembly via compression molding to a perforated PCL beam on the other side of the mesh. The resulting flat exostent (10 cm × 6 cm) was constrained around a steel cylinder while undergoing shape-setting in a water bath (40°C for 2 minutes and quenched in 4°C water), achieving its cylindrical shape (Figure (Figure33).
In vitro evaluation
This was performed to assess the biomechanical support provided by the exostent compared to healthy tracheas. Isolated exostent C-rings were evaluated in radial tension, while exostent reinforced patch-reconstructed tracheas were tested in axial tension and bending (flexion and hyperextension).
Exostent testing in radial tension
A total of five individual PCL C-rings from five separate exostents were tested in radial tension at 5mm/min to measure their radial stiffness as described in Karkhanis et al.19 The average initial radial stiffness was calculated.
Exostent reinforced trachea testing
Tracheal reconstructions (Figure (Figure3B)3B) using the patch + exostent were performed on fifteen lamb tracheas (Texas A&M Rosenthal Meat Science Center). Briefly, a 6 cm x 4 cm oval defect was created along the anterior-lateral portion of the trachea using a surgical scalpel. This defect was repaired by suturing a porcine pericardial patch (standard PT procedure). Porcine pericardium (Animal Technologies, Inc., Tyler, TX) was used instead of SIS-ECM due to its easier availability and comparable mechanical properties.20,21 Next, a 6 cm x 8 cm exostent was attached to the patch repair extraluminally with Ethicon Prolene 4-0 interrupted sutures.
Tension test
An MTS Tensile Testing Machine (MTS Insight 1) with a 10 N load cell was used for tensile testing in a test chamber containing 0.9% saline solution at 37°C. Each trachea was preconditioned by stretching to 5% of its length (five cycles at 10 mm/min). The trachea was reconstructed with the pericardial patch and re-tested in axial tension using the same protocol. The trachea was further augmented with the exostent and tested in axial tension. Load versus displacement for the fifth cycle was used to calculate the stiffness (slope of the load-displacement curve over 5–15 mm displacement). One-way analysis of variance (ANOVA) was used to compare the axial stiffness of tracheas across the different groups.
Bending test
A custom fixture was developed to model flexion and hyperextension motions using a three-point bending test (Figure (Figure4)4) on ten healthy lamb tracheas (13 cm length). This fixture uses a polyvinyl chloride (PVC) rectangular substrate (15 cm × 3.8 cm × 0.005 cm) to support the trachea as it develops a curvature during bending. The posterior trachea was attached to the substrate using Ethicon Prolene size 0 sutures passed through laser-drilled holes in the sheet (Figure (Figure4).4). This construct was positioned with the anterior trachea facing upwards for hyperextension and downward for flexion. Tracheas were immersed in 0.9% saline solution at 37°C during testing with an MTS Tensile Testing Machine (MTS Insight 1 with 10 N load cell) used to monitor bending loads generated during deflection of the center of the trachea at 10 mm/min (Figure (Figure4).4). Specimens were preconditioned (five cycles) and tested to a maximum displacement of 33.5 mm, i.e., bend angle (θ) of 45° (Figure (Figure4).4). The tracheal load in flexion and hyperextension was calculated as the difference in load for the substrate with attached trachea and the substrate without trachea for corresponding displacement. One-way ANOVA with Tukey’s test was used to compare the bending loads at 30° and 45° in both flexion and hyperextension for tracheas across the different groups.
Figure 4.
Test setup for tracheal bending stiffness evaluation in both flexion and hyperextension. PVC: polyvinyl chloride.
Results
In Vivo Evaluation of SIS-ECM
All four SIS-ECM patch animals gained weight (from 34 ± 2 kg at implant; 59 ± 1 kg at 4 months; 80 ± 1 kg at 8 months) postimplant. Bronchoscopy showed epithelialization and no granulation tissue at the SIS-ECM patch-repaired site (Figure (Figure5A).5A). Electron microscopy of the SIS-ECM patch was remarkable for the presence of mucin, secretory goblet cells, and fully formed cilia with a 9 + 2 micro-tubular arrangement suggesting motile cilia (Figure (Figure5B).5B). MRI of the SIS-ECM patch showed biomechanical integrity (i.e., no collapse), no cicatrization or granulation tissue (Figure (Figure5D).5D). The patched segments did display ellipticity of 0.87 ± 0.02 at 4 months with insignificant reduction to 0.85 ± 0.04 at 8 months (Figure (Figure5E)5E) and a tortuosity of 0.02 which remained unchanged from 4 to 8 months.
Figure 5.
A: Bronchoscopy at 4 and 8 months showed granulation-free, epithelialized patch. Histology (H&E; 40×) showed normal respiratory stratified columnar epithelium. B: Electron microscopy demonstrated the presence of mucin, goblet cells, and fully formed cilia in the small intestinal submucosa extracellular matrix (SIS-ECM) patch. C: Pericardial patch with inflammation and granulation. D: Magnetic resonance imaging (MRI) imaging of the reconstructed trachea. E: Ellipticity and tortuosity measurements of the reconstructed trachea.
Both pericardial patch control animals died early; one at 2 weeks and the other at 12 weeks from respiratory failure from airway obstruction due to granulation tissue (confirmed via bronchoscopy and gross examination at death). Epithelial edema at 6 weeks (Figure (Figure5C)5C) causing stridor and significant increase in work of breathing, confirmed that airway obstruction was the most likely cause of death.
Histology
At 4 months, the SIS-ECM patch demonstrated a structurally intact and restored architecture, with new blood vessels and matrix components (Figure (Figure6).6). Epithelial repair was robust with frequent presence of pseudostratified columnar epithelium and occasional stratified epithelium at 4 months (Figure (Figure6).6). By 8 months, the entire epithelium was remodeled into respiratory epithelium with the presence of cilia (Figure (Figure6).6). Immunohistochemistry (Ki67) indicated cell proliferation in the epithelium at 4 months which dissipated by 8 months (Figure (Figure6),6), but no sign of cartilage regeneration was seen.
Figure 6.
A: Periodic acid–Schiff (PAS) staining which signifies mucin production was noted at 8 months. Trichrome staining indicated matrix organization in small intestinal submucosa extracellular matrix (SIS-ECM) at 8 months with orientation similar to normal. B: Hematoxylin and Eosin (H&E) staining indicated mixed stratified and pseudostratified epithelium with epithelial invagin*tions noted at 4 months; complete pseudostratified epithelium with cilia noted at 8 months. Neovascularization (black arrow) was noted at both time points. Ki67 staining indicated high signifies high cell proliferation at 4 months.
In Vitro Evaluation of the Exostent
Radial stiffness
The average stiffness in radial tension for the PCL C-rings was 0.14 ± 0.02 N/mm comparing favorably with the average stiffness of lamb tracheal cartilage rings of 0.11 ± 0.07 N/mm6, i.e., the PCL C-rings were ~1.3 times that of normal/native tracheal rings.
Axial stiffness
The average axial stiffness of the healthy, patch-only reconstructed, and biosynthetic graft reconstructed trachea was 0.07 ± 0.02, 0.06 ± 0.01, and 0.08 ± 0.02 N/mm, respectively. No statistically significant differences were observed between these values.
Bending stiffness
At low bending angles/loads, the patch-reconstructed, as well as the biosynthetic graft repair tracheas demonstrate bending response equivalent to normal healthy trachea (Figure (Figure7).7). At 30° and 45° flexion, both patch and graft reconstructed tracheas had lower forces compared to healthy tracheas (p < 0.05). However, no differences were observed in forces between patch and graft reconstructed tracheas (p > 0.05). In hyperextension, no differences were observed in loads at 30° and 45° across all three groups.
Figure 7.
Mean loads at select bend angles in flexion and hyperextension for healthy and reconstructed tracheae (error bars: ± 1 standard deviation).
Visually, the biosynthetic grafted tracheas did not collapse in flexion up to bend angles of 45° whereas the patch-reconstructed tracheas collapsed at the 30° angle (Figure (Figure8).8). This was evident in Figure Figure77 where the biosynthetic grafted trachea shows an increasing force with bend angle whereas the patch-reconstructed trachea has a nearly constant force from 30°-40° followed by a decrease in load at 45°. The increase in force for healthy trachea beyond 30° was likely due to cartilage rings coming in contact.
Figure 8.
Comparison of the patch and biosynthetic graft reconstructed tracheae at 45° flexion highlighting tracheal collapse under flexion.
Discussion
Study #1, i.e., the in vivo study of the SIS-ECM biologic patch, demonstrated epithelial remodeling with cilia formation and without granulation tissue. Epithelial invagin*tions (usually seen during embryonic development, and regeneration of epithelium after injury22,23) were noted. High cell proliferation (positive Ki67 stain) was seen and correlated well with morphological changes during the epithelial invagin*tion process. These events appear to be present at 4 months and subside by 8 months.
Although mucin production was noted on PAS staining and electron microscopy with the presence of goblet cells, no submucosal glands were seen in the SIS-ECM patch. Other studies have shown that the pluripotent progenitor cells that exist in the surface airway epithelium, also have a developmental capacity for submucosal glands.22,24 Two possible reasons for the absence of submucosal glands could be (1) the smaller patch may be insufficient to generate differentiation signaling for the progenitor cells or (2) 8 months was insufficient time for the development of this relatively complex structure in this model.
Both pericardial patch control animals developed excess granulation tissue resulting in death while all SIS-ECM repair animals survived. While the SIS-ECM patch appears to perform better than pericardium it is premature to conclude that it performs better than bovine pericardium due to the lower sample sizes. SIS-ECM repaired trachea sites showed deformation (high ellipticity values; also referred to as flattening) in the repair zone. Thus, a larger patch could potentially be at risk of collapse into the trachea under negative varying airway pressures, as seen in previous patch repair studies.24,25 However, this is the purpose of the biosynthetic graft exostent.
The in vivo proof-of-concept study was limited by the small number of animals in each group. While the study duration (8 months) was based on previous studies demonstrating the remodeling of SIS-ECM in a variety of other cardiac tissues, this study may have been too short to examine tracheal remodeling in an ovine model. Bronchoscopy, histology, and immunohistochemistry results were limited to subjective observations only. Age at surgical intervention in patients with LSCTS typically from 5 months to 15 years with a large variation in the initial tracheal dimensions (from 1.0 to 4.7 mm).26 While the juvenile sheep model used in this study recapitulates some of the expected tracheal growth, the model is large compared to the expected patient population. Additionally, the biosynthetic graft will likely require a range of size options to accommodate the large range of tracheal dimensions.
Study #2, i.e., the in vitro evaluation of the exostent, shows that the biosynthetic grafted tracheas have radial and axial stiffness comparable to healthy trachea. The biosynthetic graft reconstructed tracheas also provide sufficient stiffness in flexion to accommodate curvature changes without collapse (Figure (Figure8)8) unlike the patch-only repair which clearly displayed the risk of collapse. Both patch-reconstructed and biosynthetic grafted tracheas do not significantly affect the performance of the trachea in hyperextension suggesting that the surgical procedure does not mechanically disrupt the posterior trachea.
Future testing should rigorously evaluate the device via in vitro pressure testing, especially modeling respiratory cycles combined with flexion/extension to evaluate biomechanical stability. In addition, in vitro degradation of the polymeric exostent to establish the kinetics of release of degradation byproducts, and long-term in vivo animal model studies are required to verify the mechanobiology and host response of this new graft design. In vivo studies should also evaluate the Biosynthetic graft against ST to generate a more relevant data set for evaluation of this method for clinical translation.
If successful, this Biosynthetic graft could become a potential high-value clinical option for pediatric patients with long-segment CTS, complex congenital tracheal defects, malacia, and iatrogenic/traumatic tracheal injuries (in pediatric as well as adult populations).
Footnotes
Disclosure: F.Z. is also an employee of TransMedics, Inc.
Funding: Funding was received from Texas A&M Engineering Experiment Station (B.H.), and FDA P50 SouthWest National Pediatric Devices Innovation Consortium Grant P50FD006428 (B.H.). Patch material was provided in kind by CorMatrix, Inc. with no other material or monetary funding. Parts of the study were funded by Cincinnati Children’s Hospital.
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