@article {2885, title = {An Amphiphilic Double-Brush Polymer Hydrogel for Sustained Release of Small Molecules and Biologics: Insulin Delivering-Hydrogel to Control Hyperglycemia}, year = {2022}, doi = { https://doi.org/10.1002/cnma.202200184}, author = {Dhayani, Ashish and Bej, Sujoy and Mudnakudu-Nagaraju, Kiran K and Chakraborty, Saheli and Srinath, Preetham and Kumar, Ashok H and PS, Ann Maria and Kristi, Anand and Ramakrishnan, S and Vemula PK} } @article {1935, title = {Biomaterials for topical and transdermal drug delivery in reconstructive transplantation.}, journal = {Nanomedicine (Lond)}, year = {2019}, month = {2019 Oct 23}, abstract = {

Lifelong systemic immunosuppression remains the biggest challenge in vascularized composite allotransplantation (VCA) due to the adverse effects it causes. Since VCA is a life-enhancing procedure as compared with solid organ transplant which is life-saving;\ one needs to weigh the benefits and risks carefully. Thus, there is a huge unmet clinical need to design biomaterial-based vehicles that can deliver drugs more efficiently, topically and locally to eliminate adverse effects of systemic immune suppression. This review discusses several biomaterial-based systems that have been carefully designed, conceived and attempted to make VCA a more patient compliant approach. Variety of promising preclinical studies has shown the feasibility of the approaches, and clinical trials are required to bridge the gap. Several challenges for the future and new approaches have been discussed.

}, issn = {1748-6963}, doi = {10.2217/nnm-2019-0137}, author = {Dhayani, Ashish and Kalita, Sanjeeb and Mahato, Manohar and Srinath, Preethem and Vemula, Praveen K} } @article {1605, title = {Chemical fuel-driven living and transient supramolecular polymerization.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 25}, pages = {450}, abstract = {

Temporal control over self-assembly process is a desirable trait in the quest towards adaptable and controllable materials. The ability to devise synthetic ways to control the growth, as well as decay of materials has long been a property which only the biological systems could perform seamlessly. A common synthetic strategy which works on the biological principles such as chemical fuel-driven control over temporal self-assembly profile has not been completely realized synthetically. Here we show, we filled this dearth by showing that a chemical fuel driven self-assembling system can not only be grown in a controlled manner, but it can also result in precise control over the assembly and disassembly kinetics. Herein, we elaborate strategies which clearly show that once a chemical fuel driven self-assembly is established it can be made receptive to multiple molecular cues such that the inherent growth and decay characteristics are programmed into the ensemble.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-08308-9}, author = {Jain, Ankit and Dhiman, Shikha and Dhayani, Ashish and Vemula, Praveen K and George, Subi J} } @article {1608, title = {Graft-implanted, enzyme responsive, tacrolimus-eluting hydrogel enables long-term survival of orthotopic porcine limb vascularized composite allografts: A proof of concept study.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0210914}, abstract = {

BACKGROUND: Currently, patients receiving vascularized composite allotransplantation (VCA) grafts must take long-term systemic immunosuppressive therapy to prevent immunologic rejection. The morbidity and mortality associated with these medications is the single greatest barrier to more patients being able to receive these life-enhancing transplants. In contrast to solid organs, VCA, exemplified by hand or face transplants, allow visual diagnosis of clinical acute rejection (AR), directed biopsy and targeted graft therapies. Local immunosuppression in VCA could reduce systemic drug exposure and limit adverse effects. This proof of concept study evaluated, in a large animal forelimb VCA model, the efficacy and tolerability of a novel graft-implanted enzyme-responsive, tacrolimus (TAC)-eluting hydrogel platform, in achieving long-term graft survival.

METHODS: Orthotopic forelimb VCA were performed in single haplotype mismatched mini-swine. Controls (n = 2) received no treatment. Two groups received TAC hydrogel: high dose (n = 4, 91 mg TAC) and low dose (n = 4, 49 mg TAC). The goal was to find a dose that was tolerable and resulted in long-term graft survival. Limbs were evaluated for clinical and histopathological signs of AR. TAC levels were measured in serial blood and skin tissue samples. Tolerability of the dose was evaluated by monitoring animal feeding behavior and weight.

RESULTS: Control limbs underwent Banff Grade IV AR by post-operative day six. Low dose TAC hydrogel treatment resulted in long-term graft survival time to onset of Grade IV AR ranging from 56 days to 93 days. High dose TAC hydrogel also resulted in long-term graft survival (24 to 42 days), but was not well tolerated.

CONCLUSION: Graft-implanted TAC-loaded hydrogel delays the onset of Grade IV AR of mismatched porcine forelimb VCA grafts, resulting in long term graft survival and demonstrates dose-dependent tolerability.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0210914}, author = {Fries, C Anton and Lawson, Shari D and Wang, Lin C and Slaughter, Kai V and Vemula, Praveen K and Dhayani, Ashish and Joshi, Nitin and Karp, Jeffrey M and Rickard, Rory F and Gorantla, Vijay S and Davis, Michael R} } @article {1189, title = {Local injections of tacrolimus-loaded hydrogel reduce systemic immunosuppression-related toxicity in vascularized composite allotransplantation.}, journal = {Transplantation}, year = {2018}, month = {2018 May 23}, abstract = {

BACKGROUND: Routine application of vascularized composite allotransplantation (VCA) is hampered by immunosuppression-related health comorbidities. To mitigate these we developed an inflammation-responsive hydrogel for local immunosuppression. Here we report on its long-term effect on graft survival, immunological and toxicological impact.

METHODS: Brown Norway-to-Lewis rat hind limb transplantations were treated either systemically with daily injections of 1 mg/kg tacrolimus or with subcutaneous intragraft injections of hydrogel containing 7 mg tacrolimus, every 70 days. Animals were monitored for rejection or other pathology for 280 days. Systemic and graft tacrolimus levels, regulatory T cells, and donor cell chimerism were measured periodically. At endpoint, markers for kidney, liver and metabolic state were compared to na{\"\i}ve age-matched rats.

RESULTS: Both daily systemic tacrolimus and subcutaneous intragraft tacrolimus hydrogel at 70 day intervals were able to sustain graft survival for \>280 days in 5 out of 6 recipients. In the hydrogel group, 1 graft progressed to grade 3 rejection at postoperative day (POD) 149. In systemic tacrolimus group, 1 animal was euthanized due to lymphoma on POD 275. Hydrogel treatment provided stable graft- and reduced systemic tacrolimus levels, and a 4 times smaller total tacrolimus dose compared with systemic immunosuppression. Hydrogel-treated animals showed preserved kidney function, absence of malignancies or opportunistic infections and increased hematopoietic chimerism compared to systemic immunosuppression.

CONCLUSIONS: Our findings demonstrate that localized immunosuppression with tacrolimus hydrogel is a long-term safe and reliable treatment. It may reduce the burden of systemic immunosuppression in VCA, potentially boosting the clinical application of this surgical intervention.

}, issn = {1534-6080}, doi = {10.1097/TP.0000000000002283}, author = {Dzhonova, Dzhuliya V and Olariu, Radu and Leckenby, Jonathan and Banz, Yara and Prost, Jean-Christophe and Dhayani, Ashish and Vemula, Praveen K and Voegelin, Esther and Taddeo, Adriano and Rieben, Robert} } @article {1592, title = {Local release of tacrolimus from hydrogel-based drug delivery system is controlled by inflammatory enzymes in vivo and can be monitored non-invasively using in vivo imaging.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0203409}, abstract = {

BACKGROUND: Local drug delivery systems that adjust the release of immunosuppressive drug in response to the nature and intensity of inflammation represent a promising approach to reduce systemic immunosuppression and its side effects in allotransplantation. Here we aimed to demonstrate that release of tacrolimus from triglycerol monostearate hydrogel is inflammation-dependent in vivo. We further report that by loading the hydrogel with a near-infrared dye, it is possible to monitor drug release non-invasively in an in vivo model of vascularized composite allotransplantation.

MATERIALS AND METHODS: Inflammation was induced by local challenge with lipopolysaccharides in na{\"\i}ve rats 7 days after injection of tacrolimus-loaded hydrogel in the hind limb. Tacrolimus levels in blood and tissues were measured at selected time points. A near-infrared dye was encapsulated in the hydrogel together with tacrolimus in order to monitor hydrogel deposits and drug release in vitro and in vivo in a model of vascularized composite allotransplantation.

RESULTS: Injection of lipopolysaccharides led to increased blood and skin tacrolimus levels (p = 0.0076, day 7 vs. day 12 in blood, and p = 0.0007 in treated limbs, 48 h after injection compared to controls). Moreover, lipopolysaccharides-injected animals had higher tacrolimus levels in treated limbs compared to contralateral limbs (p = 0.0003 for skin and p = 0.0053 for muscle). Imaging of hydrogel deposits and tacrolimus release was achieved by encapsulating near-infrared dye in the hydrogel for 160 days. The correlation of tacrolimus and near-infrared dye release from hydrogel was R2 = 0.6297 and R2 = 0.5619 in blood and grafts of transplanted animals respectively and R2 = 0.6066 in vitro.

CONCLUSIONS: Here we demonstrate the inflammation-responsiveness of a tacrolimus-loaded hydrogel in vivo. Moreover, we show that encapsulating a near-infrared dye in the hydrogel provides a reliable correlation of tacrolimus and dye release from the hydrogel, and an accessible non-invasive method for monitoring drug release from hydrogel deposits.

}, keywords = {Animals, Drug Delivery Systems, Humans, Hydrogels, Immunosuppressive Agents, Inflammation, Male, Rats, Rats, Inbred BN, Rats, Inbred Lew, Tacrolimus}, issn = {1932-6203}, doi = {10.1371/journal.pone.0203409}, author = {Dzhonova, Dzhuliya and Olariu, Radu and Leckenby, Jonathan and Dhayani, Ashish and Vemula, Praveen Kumar and Prost, Jean-Christophe and Banz, Yara and Taddeo, Adriano and Rieben, Robert} } @article {1201, title = {Scaling the effect of hydrophobic chain length on gene transfer properties of di-alkyl{,} di-hydroxy ethylammonium chloride based cationic amphiphiles}, journal = {RSC Adv.}, volume = {7}, year = {2017}, pages = {25398-25405}, abstract = {

The success of gene therapy critically depends on the availability of efficient transfection vectors. Cationic lipids are the most widely studied non-viral vectors. The molecular architecture of the cationic lipid determines its transfection efficiency. Variations in alkyl chain lengths of lipids influence self-assembly and liposomal fusion with the cell membrane. These factors determine the transfection ability of the lipid. Thus{,} to probe the effect of asymmetry in hydrophobic chains on transfection efficiency{,} we designed and synthesized a series of cationic lipids by systematically varying one of the two alkyl chains linked to the quaternary nitrogen centre from C18 to C10 and keeping the other alkyl C18 chain constant (Lip1818-Lip1810). Transfection studies in multiple cultured mammalian cells (CHO{,} B16F10 and HeLa) revealed that the lipids with C18:C14 and C18:C12 alkyl chains (Lip1814 \& Lip1812) showed 20-30\% higher transfection efficacies than their counterparts at 2 : 1 and 4 : 1 lipid to pDNA charge ratios. Cryo-transmission electron images showed unilamellar vesicle structures for the liposomes of lipids. Mechanistic studies involving Small Angle X-ray Scattering (SAXS) revealed that asymmetry in the hydrophobic region has a significant impact on liposomal fusion with the plasma membrane model. Collectively{,} these findings demonstrate that chain length asymmetry in the hydrophobic region of cationic lipids has an important role in their liposome-DNA interactions at optimal 2 : 1 and 4 : 1 lipid to pDNA charge ratios{,} which in turn modulates their gene transfer properties.

}, doi = {10.1039/C7RA02271A}, url = {http://dx.doi.org/10.1039/C7RA02271A}, author = {Hiwale, Ankita A. and Voshavar, Chandrashekhar and Dharmalingam, Priya and Dhayani, Ashish and Mukthavaram, Rajesh and Nadella, Rasajna and Sunnapu, Omprakash and Gandhi, Sivaraman and Naidu, V. G. M. and Chaudhuri, Arabinda and Marepally, Srujan and Vemula, Praveen Kumar} }