Dr. Rosita Primavera is a Basic Life Research Scientist at Stanford University in the Department of Radiology/Pediatric Radiology. She has a MD in chemistry and pharmaceutical technology and a PhD degree in Cellular and Molecular Biotechnologies. Dr. Primavera has documented experience on the development of nano- and micro-drug delivery systems (DDS) as well as 3D-platforms for the treatment of different diseases. She has trained in developing DDS and 3D-platforms with different materials (synthetic or natural) and employing different techniques (e.g. top/down or bottom/up fabrication). In the last few years, her research interests are focused primarily on diabetes. She has been extensively trained on how to handle and process pancreatic islets from different origins (mouse, rat and human) and she has excellent knowledge and skills to manage and perform in vitro and in vivo experiments involving diabetic animals. She is currently working on the realization of on-commanded system mimicking pancreatic islet function; and both the role of 3D-bioscaffold in pancreatic islet transplantation and the role of the mesenchymal stem cell in the setting of diabetes using novel cellular approaches (i.e. co-transplantation with islets alone or within novel bioscaffolds).
Honors & Awards
Award “Aldo La Manna” for best graduation thesis, ADRITELF CRS 2014, Florence, Italy (2014)
Education & Certifications
Postdoctoral Scholar, Interventional Regenerative Medicine and Imaging Laboratory Stanford University, Radiology Department, Stanford, CA, β cell regeneration using islet cell transplantation and construction of novel 3D porous bioscaffolds loaded with stem cells or extracellular vesicles for pancreatic islet transplantation. (2022)
Postdoctoral Scholar, Italian Institute of Technology - Genova, Nanotechnology for Precision Medicine (2019)
PhD, University of Teramo - Italy, Cellular and Molecular Biotechnology (2017)
MS, Università degli Studi “G. d’ Annunzio” Chieti-Pescara, Italia, Pharmacy (2014)
Professional Affiliations and Activities
Member, CRS Italy Local Chapter (Italian Chapter of the Controlled Release Society). (2018 - Present)
Member, ISNAFF (2020 - Present)
Member, A.D.R.I.T.E.L.F. (2020 - Present)
Member, S.C.I. (Società Chimica Italiana): Divisione di Tecnologia Farmaceutica e Divisione di Chimica Farmaceutica. (2020 - Present)
Umbilical cord mesenchymal stromal cells-from bench to bedside.
Frontiers in cell and developmental biology
2022; 10: 1006295
In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.
View details for DOI 10.3389/fcell.2022.1006295
View details for PubMedID 36313578
View details for PubMedCentralID PMC9597686
Mesenchymal stromal cells for the treatment of Alzheimer's disease: Strategies and limitations.
Frontiers in molecular neuroscience
2022; 15: 1011225
Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.
View details for DOI 10.3389/fnmol.2022.1011225
View details for PubMedID 36277497
Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours.
The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (muMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed. In orthotopic brain cancer models, generated with a conventional, reference cell line and patient-derived cells, a single muMESH application, carrying 0.75mgkg-1 of docetaxel and diclofenac, abrogates disease recurrence up to eight months after tumour resection, with no appreciable adverse effects. Without tumour resection, the muMESH increases the median overall survival (30d) as compared with the one-time intracranial deposition of docetaxel-loaded nanomedicines (15d) or 10 cycles of systemically administered temozolomide (12d). The muMESH modular structure, for the independent coloading of different molecules and nanomedicines, together with its mechanical flexibility, can be exploited to treat a variety of cancers, realizing patient-specific dosing and interventions.
View details for DOI 10.1038/s41565-021-00879-3
View details for PubMedID 33795849
Enhancing islet transplantation using a biocompatible collagen-PDMS bioscaffold enriched with dexamethasone-microplates.
Islet transplantation is a promising approach to enable type 1 diabetic patients to attain glycemic control independent of insulin injections. However, up to 60% of islets are lost immediately following transplantation. To improve this outcome, islets can be transplanted within bioscaffolds, however, synthetic bioscaffolds induce an intense inflammatory reaction which can have detrimental effects on islet function and survival. In the present study, we first improved the biocompatibility of polydimethylsiloxane (PDMS) bioscaffolds by coating them with collagen. To reduce the inflammatory response to PDMS bioscaffolds, we then enriched the bioscaffolds with dexamethasone-loaded microplates (DEX-Scaffolds). These DEX-microplates have the ability to release DEX in a sustained manner over 7 weeks within a therapeutic range that does not affect the glucose responsiveness of the islets but which minimizes inflammation in the surrounding microenvironment. The bioscaffold showed excellent mechanical properties that enabled it to resist pore collapse thereby helping to facilitate islet seeding and its handling for implantation, and subsequent engraftment, within the epididymal fat pad (EFP). Following the transplantation of islets into the EFP of diabetic mice using DEX-Scaffolds there was a return in basal blood glucose to normal values by day 4, with normoglycemia maintained for 30 days. Furthermore, these animals demonstrated a normal dynamic response to glucose challenges with histological evidence showing reduced pro-inflammatory cytokines and fibrotic tissue surrounding DEX-Scaffolds at the transplantation site. In contrast, diabetic animals transplanted with either islets alone or islets in bioscaffolds without DEX microplates were not able to regain glycemic control during basal conditions with overall poor islet function. Taken together, our data show that coating PDMS bioscaffolds with collagen, and enriching them with DEX-microplates, significantly prolongs and enhances islet function and survival.
View details for DOI 10.1088/1758-5090/abdcac
View details for PubMedID 33455953
Silicone-based bioscaffolds for cellular therapies.
Materials science & engineering. C, Materials for biological applications
2021; 119: 111615
Cellular therapy, whereby cells are transplanted to replace or repair damaged tissues and/or cells, is now becoming a viable therapeutic option to treat many human diseases. Silicones, such as polydimethylsiloxane (PDMS), consist of a biocompatible, inert, non-degradable synthetic polymer, characterized by the presence of a silicon‑oxygen‑silicon (Si-O-Si) linkage in the backbone. Silicones have been commonly used in several biomedical applications such as soft tissue implants, microfluidic devices, heart valves and 3D bioscaffolds. Silicone macroporous bioscaffolds can be made with open, interconnected pores which can house cells and facilitate the formation of a dense vascular network inside the bioscaffold to aid in its engraftment and integration into the host tissue. In this review, we will present various synthesis/fabrication techniques for silicone-based bioscaffolds and will discuss their assets and potential drawbacks. Furthermore, since cell attachment onto the surface of silicones can be limited due to their intrinsic high hydrophobicity, we will also discuss different techniques of surface modification. Finally, we will examine the physical (i.e. density, porosity, pore interconnectivity, wettability, elasticity, roughness); mechanical (tension, compression, hardness); and chemical (elemental composition-properties) properties of silicone bioscaffolds and how these can be modulated to suit the needs for specific applications.
View details for DOI 10.1016/j.msec.2020.111615
View details for PubMedID 33321658
Insulin Granule-Loaded MicroPlates for Modulating Blood Glucose Levels in Type-1 Diabetes.
ACS applied materials & interfaces
Type-1 diabetes (T1DM) is a chronic metabolic disorder resulting from the autoimmune destruction of β cells. The current standard of care requires multiple, daily injections of insulin and accurate monitoring of blood glucose levels (BGLs); in some cases, this results in diminished patient compliance and increased risk of hypoglycemia. Herein, we engineered hierarchically structured particles comprising a poly(lactic-co-glycolic) acid (PLGA) prismatic matrix, with a 20 × 20 μm base, encapsulating 200 nm insulin granules. Five configurations of these insulin-microPlates (INS-μPLs) were realized with different heights (5, 10, and 20 μm) and PLGA contents (10, 40, and, 60 mg). After detailed physicochemical and biopharmacological characterizations, the tissue-compliant 10H INS-μPL, realized with 10 mg of PLGA, presented the most effective release profile with ∼50% of the loaded insulin delivered at 4 weeks. In diabetic mice, a single 10H INS-μPL intraperitoneal deposition reduced BGLs to that of healthy mice within 1 h post-implantation (167.4 ± 49.0 vs 140.0 ± 9.2 mg/dL, respectively) and supported normoglycemic conditions for about 2 weeks. Furthermore, following the glucose challenge, diabetic mice implanted with 10H INS-μPL successfully regained glycemic control with a significant reduction in AUC0-120min (799.9 ± 134.83 vs 2234.60 ± 82.72 mg/dL) and increased insulin levels at 7 days post-implantation (1.14 ± 0.11 vs 0.38 ± 0.02 ng/mL), as compared to untreated diabetic mice. Collectively, these results demonstrate that INS-μPLs are a promising platform for the treatment of T1DM to be further optimized with the integration of smart glucose sensors.
View details for DOI 10.1021/acsami.1c16768
View details for PubMedID 34751556
- Cellular uptake and retention of nanoparticles: Insights on particle properties and interaction with cellular components MATERIALS TODAY COMMUNICATIONS 2020; 25
- Hybrid Polydimethylsiloxane Bioscaffold-Intravascular Catheter for Cellular Therapies ACS APPLIED BIO MATERIALS 2020; 3 (10): 6626–32
Hybrid Polydimethylsiloxane Bioscaffold-Intravascular Catheter for Cellular Therapies.
ACS applied bio materials
2020; 3 (10): 6626-6632
Type-1 diabetes (T1D) is caused by immune-mediated destruction of insulin-producing beta-cells, resulting in insulin deficiency and hyperglycemia. Islet transplantation is a potential treatment for T1D, but clinical implementation is hampered by islet availability and poor islet survival post-transplantation. To overcome these issues, we developed an intravascular multiside hole catheter with an interior polydimethylsiloxane (PDMS) bioscaffold capable of housing a cellular cargo. We used computational fluid dynamics to determine an optimized catheter design, which we then fabricated. Using our hybrid PDMS bioscaffold-intravascular catheter, we demonstrated that this platform can successfully maintain in vitro islet function and viability.
View details for DOI 10.1021/acsabm.0c00725
View details for PubMedID 35019389
A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation.
Advanced functional materials
2020; 30 (15)
The aim of this work was to develop, characterize and test a novel 3D bioscaffold matrix which can accommodate pancreatic islets and provide them with a continuous, controlled and steady source of oxygen to prevent hypoxia-induced damage following transplantation. Hence, we made a collagen based cryogel bioscaffold which incorporated calcium peroxide (CPO) into its matrix. The optimal concentration of CPO integrated into bioscaffolds was 0.25wt.% and this generated oxygen at 0.21±0.02mM/day (day 1), 0.19±0.01mM/day (day 6), 0.13±0.03mM/day (day 14), and 0.14±0.02mM/day (day 21). Accordingly, islets seeded into cryogel-CPO bioscaffolds had a significantly higher viability and function compared to islets seeded into cryogel alone bioscaffolds or islets cultured alone on traditional cell culture plates; these findings were supported by data from quantitative computational modelling. When syngeneic islets were transplanted into the epididymal fat pad (EFP) of diabetic mice, our cryogel-0.25wt.%CPO bioscaffold improved islet function with diabetic animals re-establishing glycemic control. Mice transplanted with cryogel-0.25wt.%CPO bioscaffolds showed faster responses to intraperitoneal glucose injections and had a higher level of insulin content in their EFP compared to those transplanted with islets alone (P<0.05). Biodegradability studies predicted that our cryogel-CPO bioscaffolds will have long-lasting biostability for approximately 5 years (biodegradation rate: 16.00±0.65%/year). Long term implantation studies (i.e. 6 months) showed that our cryogel-CPO bioscaffold is biocompatible and integrated into the surrounding fat tissue with minimal adverse tissue reaction; this was further supported by no change in blood parameters (i.e. electrolyte, metabolic, chemistry and liver panels). Our novel oxygen-generating bioscaffold (i.e. cryogel-0.25wt.%CPO) therefore provides a biostable and biocompatible 3D microenvironment for islets which can facilitate islet survival and function at extra-hepatic sites of transplantation.
View details for DOI 10.1002/adfm.201902463
View details for PubMedID 33071709
View details for PubMedCentralID PMC7567341
- A Collagen Based Cryogel Bioscaffold that Generates Oxygen for Islet Transplantation ADVANCED FUNCTIONAL MATERIALS 2020
Rapid Antibody-Based COVID-19 Mass Surveillance: Relevance, Challenges, and Prospects in a Pandemic and Post-Pandemic World.
Journal of clinical medicine
2020; 9 (10)
The aggressive outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) as COVID-19 (coronavirus disease-2019) pandemic demands rapid and simplified testing tools for its effective management. Increased mass testing and surveillance are crucial for controlling the disease spread, obtaining better pandemic statistics, and developing realistic epidemiological models. Despite the advantages of nucleic acid- and antigen-based tests such as accuracy, specificity, and non-invasive approaches of sample collection, they can only detect active infections. Antibodies (immunoglobulins) are produced by the host immune system within a few days after infection and persist in the blood for at least several weeks after infection resolution. Antibody-based tests have provided a substitute and effective method of ultra-rapid detection for multiple contagious disease outbreaks in the past, including viral diseases such as SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). Thus, although not highly suitable for early diagnosis, antibody-based methods can be utilized to detect past infections hidden in the population, including asymptomatic ones. In an active community spread scenario of a disease that can provide a bigger window for mass detections and a practical approach for continuous surveillance. These factors encouraged researchers to investigate means of improving antibody-based rapid tests and employ them as reliable, reproducible, sensitive, specific, and economic tools for COVID-19 mass testing and surveillance. The development and integration of such immunoglobulin-based tests can transform the pandemic diagnosis by moving the same out of the clinics and laboratories into community testing sites and homes. This review discusses the principle, technology, and strategies being used in antibody-based testing at present. It also underlines the immense prospect of immunoglobulin-based testing and the efficacy of repeated planned deployment in pandemic management and post-pandemic sustainable screenings globally.
View details for DOI 10.3390/jcm9103372
View details for PubMedID 33096742
Emerging Nano- and Micro-Technologies Used in the Treatment of Type-1 Diabetes.
Nanomaterials (Basel, Switzerland)
2020; 10 (4)
Type-1 diabetes is characterized by high blood glucose levels due to a failure of insulin secretion from beta cells within pancreatic islets. Current treatment strategies consist of multiple, daily injections of insulin or transplantation of either the whole pancreas or isolated pancreatic islets. While there are different forms of insulin with tunable pharmacokinetics (fast, intermediate, and long-acting), improper dosing continues to be a major limitation often leading to complications resulting from hyper- or hypo-glycemia. Glucose-responsive insulin delivery systems, consisting of a glucose sensor connected to an insulin infusion pump, have improved dosing but they still suffer from inaccurate feedback, biofouling and poor patient compliance. Islet transplantation is a promising strategy but requires multiple donors per patient and post-transplantation islet survival is impaired by inflammation and suboptimal revascularization. This review discusses how nano- and micro-technologies, as well as tissue engineering approaches, can overcome many of these challenges and help contribute to an artificial pancreas-like system.
View details for DOI 10.3390/nano10040789
View details for PubMedID 32325974
Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles.
In the present study, we created a nanoscale platform that can deliver nutrients to pancreatic islets in a controlled manner. Our platform consists of a mesoporous silica nanoparticle (MSNP), which can be loaded with glutamine (G: an essential amino acid required for islet survival and function). To control the release of G, MSNPs were coated with a polydopamine (PD) layer. With the optimal parameters (0.5 mg/mL and 0.5 h), MSNPs were coated with a layer of PD, which resulted in a delay of G release from MSNPs over 14 d (57.4 ± 4.7% release). Following syngeneic renal subcapsule islet transplantation in diabetic mice, PDG-MSNPs improved the engraftment of islets (i.e., enhanced revascularization and reduced inflammation) as well as their function, resulting in re-establishment of glycemic control. Collectively, our data show that PDG-MSNPs can support transplanted islets by providing them with a controlled and sustained supply of nutrients.
View details for DOI 10.1021/acs.nanolett.0c02576
View details for PubMedID 32909757
Engineering shape-defined PLGA microPlates for the sustained release of anti-inflammatory molecules.
Journal of controlled release : official journal of the Controlled Release Society
Over the years, nanoparticles, microparticles, implants of poly(D,l-lactide-co-glycolide) (PLGA) have been demonstrated for diverse biomedical applications. Yet, initial burst release and optimal modulation of the release profiles limit their clinical use. Here, shape-defined PLGA microPlates (μPLs) were realized for the sustained release of two anti-inflammatory molecules, the natural polyphenol curcumin (CURC) and the corticosteroid dexamethasone (DEX). Under the electron microscope, μPLs appeared as square prisms with an edge length of 20 μm. The top-down fabrication process allowed the authors to vary, readily and systematically, the μPL height from 5 to 10 μm and the PLGA mass from 1 to 5, 10 and 20 mg. 'Taller' particles realized with higher PLGA concentrations encapsulated more drug reaching on average values of about 150 pg/μPL, for both CURC and DEX. The μPL height and PLGA concentration had major effects on drug release, too. Under sink conditions, DEX release from tall μPLs at 1 h reduced from 50% to 10% and 2% for the 5, 10 and 20 mg PLGA configurations, respectively. Also, DEX was released more slowly from taller as compared to short μPLs. The opposite trend was observed for CURC, possibly for its lower hydrophobicity and molecular weight as compared to DEX. This was also confirmed by quantifying the free energy of translocation for the two drugs via molecular dynamics simulations. Finally, the anti-inflammatory activity of μPLs was tested in vitro on LPS-stimulated rat monocytes and in vivo on a murine model of UVB-induced skin burns. Both in vitro and in vivo, the expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) was significantly reduced by the application of μPLs as compared to the free compounds. In vivo, one single topical deposition of CURC-μPLs outperformed multiple, free CURC applications. This work demonstrates that geometry and polymer density can be effectively used to modulate the pharmacological performance of microparticles and mitigate the initial burst release.
View details for DOI 10.1016/j.jconrel.2019.12.039
View details for PubMedID 31899267