QUANTIFYING THE IMMUNE RESPONSE TO TISSUE ENGINEERED EXTRACELLULAR MATRIX
Bibliographic record
Abstract
Purpose: Tissue engineered heart valves have been created in order to reduce the xenoreactive immune response thought to be responsible for structural valve deterioration (SVD) of bioprosthetic heart valve replacements. Our study looks to elucidate whether tissue engineering a commercially available porcine extracellular matrix will significantly attenuate the xenoreactive immune response when compared to the wild-type matrix. Methods: Samples of whole blood, human pericardium, and bone marrow were collected from patients undergoing elective cardiac surgery. We decellularized the wild-type matrix using an established 3-day decellularization process. We then isolated human mesenchymal stem cells (hMSCs) from the collected human bone marrow that we used to recellularize the decellularized matrix. The wild-type, decellularized and recellularized matrix tissues, as well as autologous human pericardium as a control, were exposed to whole blood collected from each patient. On days 1, 3, and 5, samples of blood were collected, centrifuged and the serum stored. Enzyme Linked Immunosorbent Assay (ELISA) was performed to quantify proinflammatory cytokine production. Results: At days 1, 3, and 5, there was a significant reduction in the concentration of IL-1B cytokine production in each sample of serum exposed to decellularized and recellularized matrix when compared to the wild-type matrix, and a significant reduction in the recellularized matrix when compared to the decellularized tissue. There was a significant reduction in TNF-a concentration at days 1 and 3 for decellularized and days 3 and 5 for recellularized when compared to the wild-type matrix.Conclusion: Decllularization and recellularization with autologous hMSCs significantly attenuates the xenoreactive immune response when compared to the wild-type matrix. Therefore, tissue engineering a scaffold for bioprosthetic valve replacements may serve as an effective choice for patients to significantly reduce the xenoreactive immune response previously shown to be responsible for SVD, increasing the durability and longevity of a bioprosthetic heart valve made from this tissue engineered scaffold. University Hospital Foundation, University of Alberta. Edmonton Civic Employees Research Award. References: 1. Lung B and Vahanian A. Epidemiology of acquired valvular heart disease. Can J Cardiol. 2014; 30: 962-970 2. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG and Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet. 2006; 368: 1005-1011 3. Syedain ZH, Bradee AR, Kren S, Taylor DA and Tranquillo RT. Decellularized tissue-engineered heart valve leaflets with recellularization potential. Tissue Eng Part A. 2013; 19: 759-769 4. Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI, Taylor DA. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008 5. Jordan JE, Williams JK, Lee SJ, Raghavan D, Atala A, Yoo JJ. Bioengineered self-seeding heart valves. J Thorac Cardiovasc Surg. 2012; 143: 201-208 6. Robertson MJ, Dries-Devlin JL, Kren SM, Burchfield JS, Taylor DA. Optimizing recellularization of whole decellularized heart extracellular matrix. PLoS One. 2014; 9: e90406 7. Scarritt ME, Pashos NC, Bunnell BA. A review of cellularization strategies for tissue engineering of whole organs. Front Bioeng Biotechnol. 2015; 3: 43 8. Dignan R, O’Brien M, Hogan P, Thornton A, Fowler K, Byrne D, Stephens F, Harrocks S. Aortic valve allograft structural deterioration is associated with a subset of antibodies to human leukocyte antigens. J Heart Valve Dis. 2003; 12: 382-90; discussion 390-1 9. O’Keefe KL, Cohle SD, McNamara JE, Hooker RL,Jr. Early catastrophic stentless valve failure secondary to possible immune reaction. Ann Thorac Surg. 2011; 91: 1269-1272 10. Manji RA, Lee W, Cooper DK. Xenograft bioprosthetic heart valves: Past, present and future. Int J Surg. 2015; 23: 280-284 11. Seifert M, Bayrak A, Stolk M, Souidi N, Schneider M, Stock UA, Brockbank KG. Xeno-immunogenicity of ice-free cryopreserved porcine leaflets. J Surg Res. 2015; 193: 933-941
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".