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Biomaterials

Biomaterials - Poster Session A

Poster C3 - Biomaterial Implants for Early Detection of Transplant Vasculopathy with Minimal Invasiveness

Thursday, October 24, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  One of the main causes of long-term mortality and morbidity in heart transplant recipients is cardiac allograft vasculopathy (CAV). Vasculopathy affects the vasculature of the allograft and is thought to be caused by both immune and non-immune factors. Endothelial cells and smooth muscle cells form the innermost layers of blood vessels; proliferation of these cells in vasculopathy causes thickening of blood vessels and arteries, ultimately leading to ischemia and graft loss. However, the complete pathogenesis of vasculopathy is unknown. CAV affects 30% of patients within 5 years of transplantation and 50% within 10 years. Once diagnosed, vasculopathy cannot be cured; however, some medications and procedures can decelerate progression if diagnosed early. Unfortunately, patients are often asymptomatic. Common invasive techniques, such as biopsies, are currently the most accurate in the detection and diagnosis of vasculopathy, especially in early stages of the disease; however, they are commonly accompanied by complications. Noninvasive techniques, including various imaging methods, come with little to no complications but are less accurate and rarely detect early signs of vasculopathy. There is a pressing need for a less invasive, more accurate method of detecting vasculopathy.
Previously, we have used microporous scaffold implants made of polycaprolactone (PCL) to predict acute graft rejection. We have developed a subcutaneous implant (“scaffold”) that remotely collects immune cell biomarkers to identify pre-injury graft rejection and reduce biopsy need. In this work, we apply scaffolds to identify early transplant vasculopathy in rodent models to create a new therapeutic window to combat chronic transplant rejection.

Materials and

Methods:  In this work, we carried out an experiment to see if the scaffolds also show early signs of chronic rejection. We implanted scaffolds under the skin of donor BALB/c (B/c), C57BL/6 (B6), and B6.C-H-2bm12 (Bm12) mice; after 14 days the scaffolds became vascularized and populated with donor cells. The now donor-populated scaffolds were then transferred to B6 and B6 Rag2-/- (Rag2KO) mice, each combination resulting in a varying level of immunocompatibility (i.e. syngeneic, minor mismatch allogeneic, major mismatch allogeneic) in the immune competent B6 mice or the immune deficient Rag2KO mice. In syngeneic compatibility, and compatibility with Rag2KO recipients, we expect no vasculopathy to occur. In the minor mismatch of Bm12 to B6, we expect to see vasculopathy and in the major mismatch of B/c to B6 we expect to see acute rejection. To detect vasculopathy, we explanted three scaffolds from each mouse before transfer and at days 28 and 52 after transfer. We used flow cytometry to look at the number and phenotypes of endothelial cells, macrophages, T cells, and natural killer cells in the scaffolds. We also sectioned and stained the scaffolds via H&E, picrosirius red, and Verhoeff-Ven Gieson stain, allowing us to observe the vasculature location and assess vessel thickening.

Results, Conclusions, and Discussions: Flow cytometry indicates donor-populated scaffolds maintain donor immune cells and a hybrid donor-recipient vascular structure 50 days post-transfer in minor antigen mismatch and immunodeficient models, models representing a suppressed T cell compartment in a clinical transplant setting. Donor immune cells include macrophages and dendritic cells, and recipient NK cells increase in proportion and count over time post-transfer. With the histology library we have now developed, we will correlate these immune cell dynamics to vascularization dynamics in the donor-populated scaffolds and assess extent of vasculopathy, in addition to replicating these studies in heart transplant models.
A minimally-invasive method of detecting early signs of vasculopathy could create a new avenue of personalized transplant recipient care, such as immunosuppression regimens. Our future work will expand the application of these scaffold implants to derive biomarkers of early, actionable vasculopathy in murine heart transplant models. No diagnostic can predict graft vasculopathy, leaving clinicians without an opportunity to personalize treatments before irreversible graft damage. Identifying actionable biomarkers of and targets for vasculopathy is paramount so that clinicians can personalize immunotherapies and avoid graft loss.

Acknowledgements (Optional):