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Case Reports
. 2017 Jun;6(6):1458-1464.
doi: 10.1002/sctm.16-0443.

Tracheal Replacement Therapy with a Stem Cell-Seeded Graft: Lessons from Compassionate Use Application of a GMP-Compliant Tissue-Engineered Medicine

Martin J Elliott1, 科林·R·巴特勒12, Aikaterini Varanou-Jenkins2, Leanne Partington3, 卡拉卡瓦略3, Edward Samuel3, Claire Crowley4, Peggy Lange5, Nicholas J Hamilton2, Robert E Hynds2, Tahera Ansari5, Paul Sibbons5, Anja Fierens1, Claire McLaren6, Derek Roebuck6, Colin Wallis7, Nagarajan Muthialu1, Richard Hewitt1, David Crabbe8, Sam M Janes2, Paolo De Coppi4, Mark W Lowdell3, Martin A Birchall9
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Free PMC article
Case Reports

Tracheal Replacement Therapy with a Stem Cell-Seeded Graft: Lessons from Compassionate Use Application of a GMP-Compliant Tissue-Engineered Medicine

Martin J Elliottet al. Stem Cells Transl Med. 2017 Jun.
Free PMC article

Abstract

Tracheal replacement for the treatment of end-stage airway disease remains an elusive goal. The use of tissue-engineered tracheae in compassionate use cases suggests that such an approach is a viable option. Here, a stem cell-seeded, decellularized tissue-engineered tracheal graft was used on a compassionate basis for a girl with critical tracheal stenosis after conventional reconstructive techniques failed. The graft represents the first cell-seeded tracheal graft manufactured to full good manufacturing practice (GMP) standards. We report important preclinical and clinical data from the case, which ended in the death of the recipient. Early results were encouraging, but an acute event, hypothesized to be an intrathoracic bleed, caused sudden airway obstruction 3 weeks post-transplantation, resulting in her death. We detail the clinical events and identify areas of priority to improve future grafts. In particular, we advocate the use of stents during the first few months post-implantation. The negative outcome of this case highlights the inherent difficulties in clinical translation where preclinical in vivo models cannot replicate complex clinical scenarios that are encountered. The practical difficulties in delivering GMP grafts underscore the need to refine protocols for phase I clinical trials. Stem Cells Translational Medicine 2017;6:1458-1464.

Keywords:摘要生物人工器官;生物工程;再生medicine; Tissue engineering; Tissue scaffolds; Trachea.

Figures

Figure 1
Figure 1
Preoperative evaluation of the airway demonstrating long‐segment tracheal stenosis with a single lung.(A): Three‐dimensional (3D) model of the tracheobronchial tree demonstrating extent of stenosis (arrow) and tortuous trachea with trifurcation of the airway.(B): 3D model (left) of the trachea demonstrating multiple stents (cyan) and their relation to the stenosis (arrows); corresponding bronchogram (right).(C): Endoscopic photograph of the airway at the level of subglottis (left) and at the stenosis (right). White arrow indicates granulation tissue.(D): Preoperative computed tomography angiogram demonstrating stenotic trachea with stent in relation to arch of aorta. Blue asterisk demonstrates stent location; red hashtag indicates arch of aorta.
Figure 2
Figure 2
Strategy for delivering the cell‐seeded decellularized trachea scaffold.(A): Donor respiratory epithelial cells were isolated from mucosal biopsies taken from the nose and expanded by explant culture. Epithelial cells were passaged over 14 days prior to cryopreservation. Bone marrow aspirate was also obtained, and MSCs were expanded in culture over the same time period before cryopreservation. Prior to transplantation, cells were thawed and expanded for 7 days, seeded onto the decellularized scaffold in a bioreactor, and incubated for 48 hours.(B): Schematic representation of surgical strategy with implantation of the tracheal product in place of the diseased trachea. Abbreviation: MSCs, mesenchymal stromal cells.
Figure 3
Figure 3
Surgical transplantation of a good manufacturing practice‐compliant tissue‐engineered tracheal product.(A): Macroscopic image showing a representative segment of the resected trachea with stenosis.(B): Tracheal product immediately prior to transplantation.(C): Delivery of the cell‐seeded decellularized tracheal scaffold under cardiopulmonary bypass.(D): Tracheal product in situ with arch of aorta crossing over the anterior surface (encircled with sling). Black asterisk indicates tracheal product. Black hashtag indicates the retracted aortic arch.
Figure 4
Figure 4
Postoperative evaluation of the airway. Endoscopic view of transplanted airway at POD 1(A)and POD 6(B).(C): Bronchographic evaluation at POD 7 with PA (left) and lateral (right) views. Blue arrows show contrast within the margins of the transplanted trachea. Abbreviations: PA, posteroanterior; POD, postoperative day.
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References

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