Ciencias Exactas y Ciencias de la Salud
Permanent URI for this collectionhttps://hdl.handle.net/11285/551014
Pertenecen a esta colección Tesis y Trabajos de grado de los Doctorados correspondientes a las Escuelas de Ingeniería y Ciencias así como a Medicina y Ciencias de la Salud.
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- Local immunomodulatory strategies to enhance allogeneic pancreatic islet engraftment in a vascularized subcutaneous platform for the treatment of type 1 diabetes(Instituto Tecnológico y de Estudios Superiores de Monterrey, 2025-06-13) Campa Carranza, Jocelyn Nikita; Cuevas Díaz Durán, Raquel; emipsanchez; Nichols, Joan E.; Zavala Arcos, Judith; Lozano García, Omar; Escuela de Medicina y Ciencias de la Salud; Campus Monterrey; Grattoni, AlessandroType 1 diabetes (T1D) is an autoimmune disease marked by pancreatic β-cell destruction, leading to lifelong dependence on exogenous insulin therapy. Pancreatic islet transplantation offers a functional cure, but clinical application is limited by poor graft engraftment, hypoxia-related cell loss, and dependence on chronic systemic immunosuppression. This thesis investigates local immunomodulation approaches to improve allogeneic islet engraftment in a vascularized subcutaneous platform, the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device. Specifically, it evaluates the immunomodulatory and proangiogenic roles of mesenchymal stem cells (MSCs) and the localized delivery of clinically relevant immunosuppressive agents. Experiments were conducted in immunocompetent diabetic rats, with sex included as a biological variable. MSC-loaded NICHE devices promoted robust vascularization and improved islet engraftment, even in the context of diabetes-associated vascular dysfunction. High-dimensional immune profiling demonstrated that MSCs transiently reduced innate immune infiltration and inflammatory cytokines and preserved regulatory T cells. Sex-specific differences were observed, with female rats exhibiting improved vascularization and immune regulation. Additionally, local immunosuppression was explored revealing different immunomodulatory profiles, and drug retention at the graft site with minimal systemic exposure. Together, this work supports a combinatorial local immunomodulation approach integrating MSCs and targeted immunosuppression. The NICHE platform provides a clinically relevant strategy for long-term islet engraftment without systemic immunosuppression, advancing safer, more effective therapies for T1D.
- Implantable platform with in-situ vascularization and localized immunosuppression for allogeneic cell transplantation.(Instituto Tecnológico y de Estudios Superiores de Monterrey, 2021-04) Páez Mayorga,Jesús; PAEZ MAYORGA, JESUS; 778572; tolmquevedo; Nichols, Joan E.; Cuevas Díaz Durán, Raquel; Guajardo Flores, Daniel; School of Engineering and Sciences; Campus Monterrey; Grattoni, AlessandroAllogeneic islet transplantation for diabetes management faces the challenge of preventing immune rejection while maintaining enough graft oxygenation for proper metabolic function. Islet encapsulation within membranes impermeable to immune cells prevents rejection at the expense of optimal graft oxygenation. Conversely, direct vascularization avoids hypoxia but requires systemic administration of toxic immunosuppressive drugs. To overcome this problem, we developed the subcutaneously implantable NICHE platform, which integrates in situ graft vascularization and local immunosuppressant delivery, for long-term islet engraftment. NICHE, 3D-printed in nylon, is comprised of independent drug and cell reservoirs separated by a nanoporous membrane. The membrane allows steady local diffusion of immunosuppressant from the drug reservoir into the cell reservoir. Enhanced NICHE vascularization was assessed using mesenchymal stem cells (MSC) and platelet rich plasma (PRP) in rats and non-human primates (NHP). Tunability of antibody and peptide release from NICHE was tested in vitro. Transplantation of allogeneic islets into prevascularized NICHE with localized co-delivery of anti-lymphocyte serum (ALS) and CTLA4Ig was evaluated in immunocompetent diabetic rats. NICHE loaded with MSC had dense vascularity within the cell reservoir by 4 weeks of subcutaneous implantation in rats and NHP. In vitro drug release was tuned via modification of membrane exchange area and drug concentration loaded. In diabetic rats, localized co-delivery of ALS and CTLA4Ig protected allogeneic islets, resulting in reversal to euglycemic state for at least 60 days. Transplanted rats with NICHE responded to glucose challenge comparable to healthy controls and had significantly higher c-peptide levels than no-implant diabetic controls, demonstrating full graft function. ALS-CLTA4Ig co-delivery via NICHE localized drug at the transplant site with limited accumulation in plasma and peripheral tissues, avoiding potential toxicity. Moreover, circulating lymphocyte population remained intact, indicating rats were not systemically immunosuppressed. NICHE is an effective platform for islet allotransplantation with promising adaptability for use with other cell types and pathologies.