Engineering the vasculature for islet transplantation

Abstract

The microvasculature in the pancreatic islet is highly specialized for glucose sensing and insulin secretion. Although pancreatic islet transplantation is a potentially life-changing treatment for patients with insulin-dependent diabetes, a lack of blood perfusion reduces viability and function of newly transplanted tissues. Functional vasculature around an implant is not only necessary for the supply of oxygen and nutrients but also required for rapid insulin release kinetics and removal of metabolic waste. Inadequate vascularization is particularly a challenge in islet encapsulation. Selectively permeable membranes increase the barrier to diffusion and often elicit a foreign body reaction including a fibrotic capsule that is not well vascularized. Therefore, approaches that aid in the rapid formation of a mature and robust vasculature in close proximity to the transplanted cells are crucial for successful islet transplantation or other cellular therapies. In this paper, we review various strategies to engineer vasculature for islet transplantation. We consider properties of materials (both synthetic and naturally derived), prevascularization, local release of proangiogenic factors, and co-transplantation of vascular cells that have all been harnessed to increase vasculature. We then discuss the various other challenges in engineering mature, long-term functional and clinically viable vasculature as well as some emerging technologies developed to address them. The benefits of physiological glucose control for patients and the healthcare system demand vigorous pursuit of solutions to cell transplant challenges. STATEMENT OF SIGNIFICANCE: Insulin-dependent diabetes affects more than 1.25 million people in the United States alone. Pancreatic islets secrete insulin and other endocrine hormones that control glucose to normal levels. During preparation for transplantation, the specialized islet blood vessel supply is lost. Furthermore, in the case of cell encapsulation, cells are protected within a device, further limiting delivery of nutrients and absorption of hormones. To overcome these issues, this review considers methods to rapidly vascularize sites and implants through material properties, pre-vascularization, delivery of growth factors, or co-transplantation of vessel supporting cells. Other challenges and emerging technologies are also discussed. Proper vascular growth is a significant component of successful islet transplantation, a treatment that can provide life-changing benefits to patients.

Keywords: Endothelial cell; Islet transplantation; Microvasculature; Type 1 diabetes; Vascularization.

Figure 1.. Mass transfer to islets is limited by isolation and encapsulation.

Compared to the native pancreas (a), islets experience reduced diffusion to the majority of cells (especially in the core of the cell mass) as a result of loss of blood perfusion following isolation from the acinar tissue (b). Furthermore, encapsulation of any kind (microencapsulation shown here) increases the distance of islet cells to the surrounding fluid or blood vessels (c). Dark blue represents greater mass transport. Drawings not to scale.

Figure 2.. Material properties that influence vascularization.

The thickness of the avascular fibrotic layer (shown in light red) can be reduced by constructing an implant that allows cell migration into the membrane (a). Larger pores can facilitate more blood vessel investment than pores that are only sufficiently large enough to allow blood vessels to form (b). Increases in nanotopographical roughness can increase vascularization compared to smooth substrates (c).

Figure 3.. ECM materials that can be used to scaffold and vascularize transplanted islets.

Fibrin scaffolds are polymerized from fibrinogen present in the blood plasma (a). Matrigel is isolated from a murine sarcoma (a). Collagen can be isolated from many sources, with skin shown here as an example (a). Decellularized pancreatic tissue may be a natural scaffold for islet transplant (b). Matrix materials can be selected and combined to promote islet vascularization and health.

Figure 4.. Preparing a site by prevascularization to improve engraftment.

Preimplantation of a material stimulates vascular enrichment (a). The islets can then be introduced into the preimplanted device (b) or the device can be removed to create a space left by the device that the islets can be introduced into (c). All of these approaches result in a space for the islets that has a greater vascular supply at the time of transplantation than an unprepared site.

Figure 5.. Release of angiogenic factors to drive implant angio- or arteriogenesis.

Angiogenesis is the formation of new capillary sprouts from existing vessels and can be driven by factors such as VEGF (a). Arteriogenesis is the maturation of blood vessels, often characterized by the addition of support cells to an endothelial tube and the increase in lumen diameter. Arteriogenesis can be driven by factors such as PDGF-BB (a). Multiple factors can also be sequentially released (e.g., VEGF then S1P, VEGF then PDGF) to push both of these vessel network expansion paradigms (a,b).

Figure 6.. Co-transplantation of vascularization supporting cells to improve engraftment.

Vascularization supporting cells can be mixed with islets or cell aggregates before transplantation (a). Vascularization supporting cells can be included with hormone-producing cells during aggregation (b). Vascularization supporting cells can be coated on islets or cell aggregates before transplantation (c). It is also possible to coat vascularization supporting cells on or in islet-matrix modules (d).

Figure 7.. Organization of vascular structures in engineered environments.

Engineering of vascular regeneration can be accomplished utilizing some emerging approaches. Tubular voids in constructs can be formed and then endothelialized (a). Three-dimensional printing can be used to arrange vascular tissues and the islets or cell clusters in logical patterns (b). Endothelialized modules can be formed in vitro using microfabricated molds.