Engineering Modular, Oxygen‐Generating Microbeads for the In Situ Mitigation of Cellular Hypoxia

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Abstract

Insufficient oxygenation is a key obstacle in the design of clinically scalable tissue‐engineered grafts. In this work, an oxygen‐generating composite material, termed OxySite, is created through the encapsulation of calcium peroxide (CaO ₂) within polydimethylsiloxane and formulated into microbeads for ease in tissue integration. Key material parameters of reactant loading, porogen addition, microbead size, and an outer rate‐limiting layer are modulated to characterize oxygen generation kinetics and their suitability for cellular applications. In silico models are developed to predict the local impact of different OxySite microbead formulations on oxygen availability within an idealized cellular implant. Promising OxySite microbead variants are subsequently coencapsulated with murine β‐cells within macroencapsulation devices, resulting in improved cellular metabolic activity and function under hypoxic conditions when compared to controls. Additionally, the coinjection of optimized OxySite microbeads with murine pancreatic islets within a confined transplant site demonstrates ease of integration and improved primary cell function. These works highlight the broad translatability delivered by this new oxygen‐generating biomaterial format, whereby the modularity of the material provides customization of the oxygen source to the specific needs of the cellular implant.

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Pathological angiogenesis is a hallmark of cancer and various ischaemic and inflammatory diseases. Concentrated efforts in this area of research are leading to the discovery of a growing number of pro- and anti-angiogenic molecules, some of which are already in clinical trials. The complex interactions among these molecules and how they affect vascular structure and function in different environments are now beginning to be elucidated. This integrated understanding is leading to the development of a number of exciting and bold approaches to treat cancer and other diseases. But owing to several unanswered questions, caution is needed.

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Tissue engineering has been an active field of research for several decades now. However, the amount of clinical applications in the field of tissue engineering is still limited. One of the current limitations of tissue engineering is its inability to provide sufficient blood supply in the initial phase after implantation. Insufficient vascularization can lead to improper cell integration or cell death in tissue-engineered constructs. This review will discuss the advantages and limitations of recent strategies aimed at enhancing the vascularization of tissue-engineered constructs. We will illustrate that combining the efforts of different research lines might be necessary to obtain optimal results in the field.

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Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.

A.M. Shapiro, Jonathan R.T. Lakey, Edmond Ryan … (2000)

Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year. Seven consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization. All seven patients quickly attained sustained insulin independence after transplantation of a mean (+/-SD) islet mass of 11,547+/-1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors to achieve sustained insulin independence. The mean glycosylated hemoglobin values were normal after transplantation in all recipients. The mean amplitude of glycemic excursions (a measure of fluctuations in blood glucose concentrations) was significantly decreased after the attainment of insulin independence (from 198+/-32 mg per deciliter [11.1+/-1.8 mmol per liter] before transplantation to 119+/-37 mg per deciliter [6.7+/-2.1 mmol per liter] after the first transplantation and 51+/-30 mg per deciliter [2.8+/-1.7 mmol per liter] after the attainment of insulin independence; P<0.001). There were no further episodes of hypoglycemic coma. Complications were minor, and there were no significant increases in lipid concentrations during follow-up. Our observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.