Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum.

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.

Rational Engineering of Islet Tolerance via Biomaterial-Mediated Immune Modulation.

Type 1 diabetes (T1D) onset is characterized by an autoimmune attack on ß islet cells within the pancreas, preventing the insulin secretion required to maintain glucose homeostasis. Targeted modulation of key immunoregulatory cell populations is a promising strategy to restore tolerance to ß cells. This strategy can be used to prevent T1D onset or reverse T1D with transplanted islets. To this end, drug delivery systems can be employed to transport immunomodulatory cargo to specific cell populations that inhibit autoreactive T cell-mediated destruction of the ß cell mass. The rational engineering of biomaterials into nanoscale and microscale drug carriers can facilitate targeted interactions with immune cells. The physicochemical properties of the biomaterial, the delivered immunomodulatory agent, and the target cell populations are critical variables in the design of these delivery systems. In this review, we discuss recent biomaterials-based drug delivery approaches to induce islet tolerance and the need to consider both immune and metabolic markers of disease progression.

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability.

Standard oral rapamycin (that is, Rapamune) administration is plagued by poor bioavailability and broad biodistribution. Thus, this pleotropic mammalian target of rapamycin (mTOR) inhibitor has a narrow therapeutic window and numerous side effects and provides inadequate protection to transplanted cells and tissues. Furthermore, the hydrophobicity of rapamycin limits its use in parenteral formulations. Here, we demonstrate that subcutaneous delivery via poly(ethylene glycol)-b-poly(propylene sulfide) polymersome nanocarriers significantly alters rapamycin's cellular biodistribution to repurpose its mechanism of action for tolerance, instead of immunosuppression, and minimize side effects. While oral rapamycin inhibits T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes modulate antigen presenting cells in lieu of T cells, significantly improving maintenance of normoglycemia in a clinically relevant, major histocompatibility complex-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of a rationally designed nanocarrier to re-engineer the immunosuppressive mechanism of a drug by controlling cellular biodistribution.

Clinical Relevance of Pre-Existing and Treatment-Induced Anti-Poly(Ethylene Glycol) Antibodies.

Abstract: Poly(ethylene glycol) (PEG) is a nontoxic, hydrophilic polymer that is often covalently attached to proteins, drugs, tissues, or materials; a procedure commonly referred to as PEGylation. PEGylation improves solubility, circulation time, and reduces immunogenicity of therapeutic molecules. Currently, there are 21 PEGylated drugs approved by the Food and Drug Administration (FDA), and more in the developmental stage. In addition to the polymer's applications in the clinic, PEG is widely used as a solvent and emulsifying agent in the formulation of cosmetics, cleaning, and personal care products. Due to the ubiquitous presence of the polymer in everyday products, patients can develop antibodies against PEG (αPEG Abs) that can be problematic when a PEGylated drug is administered. These αPEG Abs can provoke hypersensitivity reactions, accelerated drug clearance, and decreased therapeutic efficacy. Herein, we review how the prevalence of PEG in everyday products has induced αPEG Abs within the general public as well as the effect of these Abs on the performance of PEGylated therapeutics. We will focus on clinical manifestations following the administration of PEGylated drugs. Lay Summary: Poly(ethylene glycol) (PEG) is a polymer found in products including cosmetics, personal care products, cleaning agents, medicine, and food. Due to the prevalence of PEG, people can develop antibodies (αPEG Abs) against the polymer, which recognize PEG as foreign. Of note, PEG is frequently incorporated into drug formulations to improve therapeutic efficacy. Complications can arise when a patient receiving a PEGylated drug has previously developed αPEG Abs from interactions with PEG in everyday products. The presence of high concentrations of αPEG Abs in blood can result in decreased treatment efficacy and allergic reactions to a wide range of therapeutics.

Evaluation of Patient Factors Associated With Achieving Goal Hemoglobin A1c in Collaborative Drug Therapy Management Ambulatory Care Clinics by Clinical Pharmacists: A Retrospective Chart Review.

Background: Literature has shown the positive impact pharmacists have on diabetic outcome measures through collaborative drug therapy management (CDTM). There is minimal literature evaluating characteristics and clinical factors of patients who benefit from CDTM diabetes clinics by pharmacists. Objective: Identify patient characteristics and clinical factors that may be associated with patients who reach goal hemoglobin A1c (HbA1c) of <7% at discharge by pharmacists practicing under CDTM agreements. Methods: This retrospective chart review included patients referred to pharmacist CDTM clinics for type 2 diabetes with an HbA1c goal of <7%. Data were extracted from the electronic medical record at enrollment and discharge. Results: Of the 228 patients included, 84 achieved a goal HbA1c of <7%. Factors predictive of patient success were Asian ethnicity (odds ratio [OR] = 19.32), baseline HbA1c of 7% to 7.9% (OR = 2.34), enrolled in clinic for 5 to 6 months (OR = 2.06), in-person visit every 4 to <8 weeks (OR = 3.06), not on insulin initially or at discharge (OR = 1.79, OR = 2.02), or discharged on a glucagon-like peptide-1 receptor agonist (OR = 1.83). Factors predictive of not reaching goal were Black or African American ethnicity (OR = 0.42), <5 encounters of any type (OR = 0.44), an encounter of any type every 8 weeks or more (OR = 0.08), or discharged on a sodium-glucose cotransporter-2 inhibitor (OR = 0.27). Conclusion: Several clinical and demographic factors were identified that influenced a patient's ability to reach a goal HbA1c of <7%. The results of this study may be applied to further advance pharmacist-run clinics in optimizing diabetes care for patients.

Factors that assist and hinder efforts towards recovery from eating disorders: A comparison of collegiate female athletes and non-athletes.

This study compared female intercollegiate athletes' and non-athletes' experiences of working towards recovery from an eating disorder. Participants (55 athletes, 99 non-athletes) responded to open-ended questions about factors that influenced their progress towards recovery. Both subgroups reported that Supportive Relationships and Cognitive/Emotional Shifts were most helpful. The third most frequent helpful factor for athletes was Sport Performance Concerns, for non-athletes it was Treatment. Athletes' most frequent hindering factors were Negative Emotions/Cognitions, Sport Pressures, and Hurtful Modelling, while non-athletes reported Negative Emotions/Cognitions, Lack of Support, and Hurtful Modelling. Sport-specific factors were among the most common themes in athletes' responses; therefore, athletes' recovery experiences and treatment needs appear unique.

Fundamental care guided by the Careful Nursing Philosophy and Professional Practice Model©.

AIMS AND OBJECTIVES: To propose the Careful Nursing Philosophy and Professional Practice Model© as a conceptual and practice solution to current fundamental nursing care erosion and deficits. BACKGROUND: There is growing awareness of the crucial importance of fundamental care. Efforts are underway to heighten nurses' awareness of values that motivate fundamental care and thereby increase their attention to effective provision of fundamental care. However, there remains a need for nursing frameworks which motivate nurses to bring fundamental care values to life in their practice and strengthen their commitment to provide fundamental care. DESIGN: This descriptive position paper builds on the Careful Nursing Philosophy and Professional Practice Model© (Careful Nursing). Careful Nursing elaborates explicit nursing values and addresses both relational and pragmatic aspects of nursing practice, offering an ideal guide to provision of fundamental nursing care. METHOD: A comparative alignment approach is used to review the capacity of Careful Nursing to address fundamentals of nursing care. CONCLUSIONS: Careful Nursing provides a value-based comprehensive and practical framework which can strengthen clinical nurses' ability to articulate and control their practice and, thereby, more effectively fulfil their responsibility to provide fundamental care and measure its effectiveness. RELEVANCE TO CLINICAL PRACTICE: This explicitly value-based nursing philosophy and professional practice model offers nurses a comprehensive, pragmatic and engaging framework designed to strengthen their control over their practice and ability to provide high-quality fundamental nursing care.

Enhanced elastin synthesis and maturation in human vascular smooth muscle tissue derived from induced-pluripotent stem cells.

Obtaining vascular smooth muscle tissue with mature, functional elastic fibers is a key obstacle in tissue-engineered blood vessels. Poor elastin secretion and organization leads to a loss of specialization in contractile smooth muscle cells, resulting in over proliferation and graft failure. In this study, human induced-pluripotent stem cells (hiPSCs) were differentiated into early smooth muscle cells, seeded onto a hybrid poly(ethylene glycol) dimethacrylate/poly (l-lactide) (PEGdma-PLA) scaffold and cultured in a bioreactor while exposed to pulsatile flow, towards maturation into contractile smooth muscle tissue. We evaluated the effects of pulsatile flow on cellular organization as well as elastin expression and assembly in the engineered tissue compared to a static control through immunohistochemistry, gene expression and functionality assays. We show that culturing under pulsatile flow resulted in organized and functional hiPSC derived smooth muscle tissue. Immunohistochemistry analysis revealed hiPSC-smooth muscle tissue with robust, well-organized cells and elastic fibers and the supporting microfibril proteins necessary for elastic fiber assembly. Through qRT-PCR analysis, we found significantly increased expression of elastin, fibronectin, and collagen I, indicating the synthesis of necessary extracellular matrix components. Functionality assays revealed that hiPSC-smooth muscle tissue cultured in the bioreactor had an increased calcium signaling and contraction in response to a cholinergic agonist, significantly higher mature elastin content and improved mechanical properties in comparison to the static control. The findings presented here detail an effective approach to engineering elastic human vascular smooth muscle tissue with the functionality necessary for tissue engineering and regenerative medicine applications. STATEMENT OF SIGNIFICANCE: Obtaining robust, mature elastic fibers is a key obstacle in tissue-engineered blood vessels. Human induced-pluripotent stem cells have become of interest due to their ability to supplement tissue engineered scaffolds. Their ability to differentiate into cells of vascular lineages with defined phenotypes serves as a potential solution to a major cause of graft failure in which phenotypic shifts in smooth muscle cells lead to over proliferation and occlusion of the graft. Herein, we have differentiated human induced-pluripotent stem cells in a pulsatile flow bioreactor, resulting in vascular smooth muscle tissue with robust elastic fibers and enhanced functionality. This study highlights an effective approach to engineering elastic functional vascular smooth muscle tissue for tissue engineering and regenerative medicine applications.

Engineered human vascularized constructs accelerate diabetic wound healing.

Stem cell-based therapy is emerging as a promising approach for chronic diabetic wounds, but strategies for optimizing both cellular differentiation and delivery remain as major obstacles. Here, we study bioengineered vascularized constructs as a therapeutic modality for diabetic wound healing. We developed a wound model in immunodeficient rodent and treated it with engineered vascularized constructs from endothelial progenitors or early vascular cells-derived from human induced pluripotent stem cells (hiPSCs) reprogrammed either from healthy donor or type-1 diabetic patient. We found that all vascularized constructs expedited wound closure and reperfusion, with endothelial progenitor constructs having the earliest maximum closure rate followed closely by healthy and diabetic hiPSC-derivative constructs. This was accompanied by rapid granulation layer formation and regression in all vascularized construct groups. Macrophage infiltration into the hydrogel matrix occurred during early stages of healing, seeming to facilitate rapid neovascularization of the wound that could then better persist in the vascularized constructs. Blood perfusion of the human vasculature could be detected after three days, indicating rapid integration with the host vasculature. Overall, we propose a potential therapeutic strategy using allograft or autologous vascularized constructs to treat type-1 diabetic wounds. This approach highlights the unprecedented prospects of designing patient-specific stem cell therapy.

Acellular Hydrogels for Regenerative Burn Wound Healing: Translation from a Porcine Model.

Currently available skin grafts and skin substitutes for healing following third-degree burn injuries are fraught with complications, often resulting in long-term physical and psychological sequelae. Synthetic treatment that can promote wound healing in a regenerative manner would provide an off-the-shelf, non-immunogenic strategy to improve clinical care of severe burn wounds. Here, we demonstrate the vulnerary efficacy and accelerated healing mechanism of a dextran-based hydrogel in a third-degree porcine burn model. The model was optimized to allow examination of the hydrogel treatment for clinical translation and its regenerative response mechanisms. Hydrogel treatment accelerated third-degree burn wound healing by rapid wound closure, improved re-epithelialization, enhanced extracellular matrix remodeling, and greater nerve reinnervation, compared with the dressing-treated group. These effects appear to be mediated through the ability of the hydrogel to facilitate a rapid but brief initial inflammatory response that coherently stimulates neovascularization within the granulation tissue during the first week of treatment, followed by an efficient vascular regression to promote a regenerative healing process. Our results suggest that the dextran-based hydrogels may substantially improve healing quality and reduce skin grafting incidents and thus pave the way for clinical studies to improve the care of severe burn injury patients.

Models of initial training and pathways to registration: a selective review of policy in professional regulation.

AIM: To provide a synthesis of literature on international policy concerning professional regulation in nursing and midwifery, with reference to routes of entry into training and pathways to licensure. BACKGROUND: Internationally, there is evidence of multiple points of entry into initial training, multiple divisions of the professional register and multiple pathways to licensure. EVALUATION: Policy documents and commentary articles concerned with models of initial training and pathways to licensure were reviewed. Item selection, quality appraisal and data extraction were undertaken and documentary analysis was performed on all retrieved texts. KEY ISSUES: Case studies of five Western countries indicate no single uniform system of routes of entry into initial training and no overall consensus regarding the optimal model of initial training. CONCLUSIONS: Multiple regulatory systems, with multiple routes of entry into initial training and multiple pathways to licensure pose challenges, in terms of achieving commonly-agreed understandings of practice competence. IMPLICATIONS FOR NURSING MANAGEMENT: The variety of models of initial training present nursing managers with challenges in the recruitment and deployment of personnel trained in many different jurisdictions. Nursing managers need to consider the potential for considerable variation in competency repertoires among nurses trained in generic and specialist initial training models.