Objective
The objective of this study is to overcome current clinical hurdles facing islet transplantation, by employing two graft localized therapeutic delivery systems, composed of biomaterials (PLGA), to enhance islet graft survival and function when transplanted into the subcutaneous site (under the skin). Our first system employs our retrievable subcutaneous bio-active scaffold and our second system will expand and utilize our islet graft localized PLGA drug eluting microparticle approach to evaluate the impact of targeting peri-and acute post-transplant immune modulation, insulin secretion and cell death to augment islet engraftment. We hypothesize that tethering our novel scaffold system and drug eluting microparticle platform will allow us to create a highly vascularized and optimal space to permit long-term graft function.
Background Rationale
One obstacle for successful clinical islet cell transplantation is the poor survival of the islets in the immediate post-transplant period. The cause of this is largely due to a poor supply of blood vessels in the transplant site. The objective of this study is to overcome this clinical hurdle facing islet transplantation, by employing two graft localized therapeutic delivery systems, composed of biomaterials (PLGA), to enhance islet graft survival and function when transplanted into the subcutaneous site (under the skin). Our first system employs our retrievable subcutaneous bio-active scaffold and our second system will expand and utilize our islet graft localized PLGA drug eluting microparticle approach to evaluate the impact of targeting peri-and acute post-transplant immune modulation, insulin secretion and cell death to augment islet engraftment. We hypothesize that tethering our novel scaffold system and drug eluting microparticle platform will allow us to create a highly vascularized and optimal space to permit long-term graft function.
Description of Project
The objective of this study is to overcome current clinical hurdles facing islet transplantation, by employing two graft localized therapeutic delivery systems, composed of biomaterials (PLGA), to enhance islet graft survival and function when transplanted into the subcutaneous site (under the skin). Our first system employs our retrievable subcutaneous bio-active scaffold and our second system will expand and utilize our islet graft localized PLGA drug eluting microparticle approach to evaluate the impact of targeting peri-and acute post-transplant immune modulation, insulin secretion and cell death to augment islet engraftment. We hypothesize that tethering our novel scaffold system and drug eluting microparticle platform will allow us to create a highly vascularized and optimal space to permit long-term graft function.
SPECIFIC AIMS:
Aim 1: Using bio-active PLGA scaffolds, implanted subcutaneously, we will: 1) examine the simultaneous and sequential release of trophic factors targeting blood vessel formation and maturation, 2) determine optimal dosage and release kinetics of these tropic factors, and 3) perform detailed characterization and kinetics of subsequent blood vessel formation.
Aim 2: Based on Aim 1, we will employ bio-active PLGA scaffolds to enhance primary engraftment of mouse, neonatal porcine and human islets in mice without an immune system.
Aim 3: Combine the optimal transplantation strategy elucidated in Aim 2, with drug-eluting microparticles targeting inflammation, insulin secretion and cell death to: 1) further enhance primary engraftment of mouse islets as well as neonatal porcine and human islets transplanted in immuno-compromised mice and 2) improve the survival of murine islet allografts.
Aim 4: Test the therapeutic potential of combining optimized bio-active subcutaneous scaffolds (Aim 1 & 2) and with graft localized microparticles targeting cell death (Aim 3) and immunomodulation to protect murine islet allografts without systemic immunosuppression.
Aim 5: Scale and define the efficacy of our combined approach (Aim 4) to enhance islet allograft survival in a clinically relevant large animal model.
Anticipated Outcome
We anticipate that our novel approach for using our novel two graft localized therapeutic delivery systems will lead to long-term durable
islets graft function as well as circumvent the complications associated with systemic immune-suppression.
Relevance to T1D
We hypothesize that our novel approach for using our novel two graft localized therapeutic delivery systems will lead to long-term durable islet graft function
and thereby broaden the spectrum of T1D patients eligible to receive curative islet cell replacement therapies.