Origin of insulin secreted from islet-like cell clusters derived from murine embryonic stem cells.

Islet-like cell clusters (ILCCs) were derived from murine embryonic stem cells using a slightly modified version of the protocol originally described by Lumelsky et al. in 2001. Analysis with enzyme-linked immunosorbent assays (ELISAs) that distinguish human from murine insulin demonstrated that insulin released from these ILCCs, upon initial in vitro glucose challenge, was of non-murine origin and in fact corresponded to the species of insulin, human or bovine, that had been added to the culture media used to derive ILCCs. This finding convincingly supports the hypothesis that ILCCs are not synthesizing insulin de novo, but rather simply regurgitating insulin taken up during tissue culture. In further experiments, ILCCs were derived in media in which insulin had been replaced by IGF-I with which it shares a common signaling pathway. These ILCCs failed to release any detectable insulin. In contrast, ILCCs produced by various protocols stained positive (dithizone and immunoselective antibodies) for intracellular insulin and, in some cases, C-peptide. Despite the presence of at least some level of de novo, synthesized insulin in ILCCs, the majority of insulin released by ILCCs was sequestered from the exogenous medium.

The growth of tissue engineering.

This report draws upon data from a variety of sources to estimate the size, scope, and growth rate of the contemporary tissue engineering enterprise. At the beginning of 2001, tissue engineering research and development was being pursued by 3,300 scientists and support staff in more than 70 startup companies or business units with a combined annual expenditure of over $600 million. Spending by tissue engineering firms has been growing at a compound annual rate of 16%, and the aggregate investment since 1990 now exceeds $3.5 billion. At the beginning of 2001, the net capital value of the 16 publicly traded tissue engineering startups had reached $2.6 billion. Firms focusing on structural applications (skin, cartilage, bone, cardiac prosthesis, and the like) comprise the fastest growing segment. In contrast, efforts in biohybrid organs and other metabolic applications have contracted over the past few years. The number of companies involved in stem cells and regenerative medicine is rapidly increasing, and this area represents the most likely nidus of future growth for tissue engineering. A notable recent trend has been the emergence of a strong commercial activity in tissue engineering outside the United States, with at least 16 European or Australian companies (22% of total) now active.

Demographic scope and economic magnitude of contemporary organ replacement therapies.

This analysis draws upon a variety of sources to provide a tally of the number of patients receiving organ replacement therapies and the costs associated with the provision of such therapies. Constituent data were available from treatment-specific patient registries, peer reviewed reports in scientific literature, business publications, and industry sources. The magnitude and economic scope of the contemporary organ replacement enterprise were found to be much larger than is generally recognized. In the year 2000, the lives of over 20 million patients will be sustained, supported, or significantly improved by functional organ replacement. The impacted population grows at over 10% per year. Worldwide, first year and follow-up costs of organ prosthesis exceeds $300 billion US dollars per year and represents between 7 and 8% of total worldwide health care spending. Remarkably, in the United States, the costs of therapies enabled by organ replacement technology exceed 1% of the Gross Domestic Product. These findings constitute an incontestable tribute to the scientific significance and medical impact of the still nascent field of substitutive medicine. At the same time, the enormous magnitude of resources dedicated to organ replacement raises several issues related to overall cost effectiveness of current modalities and raises challenges and opportunities for future technical developments.

The case for financial incentives to encourage organ donation.

The existing system of organ procurement has failed in its mission of providing an adequate number of organs for transplantation. The organ shortfall results in diminished life expectancy and quality of life for dialysis patients and in increased mortality for patients with end-stage cardiac disease and liver failure who are unable to obtain transplants. Oft-repeated arguments against sale of human organs do not stand up to careful examination, and seem anachronistic in the context of widespread current acceptance of financial incentives for tissue donation in analogous fields, such as reproductive medicine. This essay advocates the staged introduction of a reward-based system of organ donation, initially for cadaveric harvesting and, possibly, later for living donation. Although imperfect, the proposed approach would represent a significant improvement over the status quo.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Significant changes in extracorporeal membranes have occurred over the past five decades in which hemodialysis (HD) has been available as a therapy for both acute renal failure (ARF) and end-stage renal disease (ESRD). For cellulosic membranes, these changes have included a reduction in thickness, hydroxyl group substitution, and an increase in pore size. These modifications have resulted in enhanced efficiency of small solute removal, a broader spectrum of overall solute removal, and an attenuation of complement activation in comparison to the thick, unsubstituted cellulosic membranes of low permeability used in the early days of HD therapy. Synthetic membranes, originally developed specifically for use in high-flux HD and hemofiltration, have also evolved during this same time period. In fact, the initially clear distinction between low-flux regenerated cellulosic and high-flux synthetic membranes has become blurred, as membrane formulators have developed products designed to appeal to enthusiasts for both membrane formats. The purpose of this review is to characterize both the solute removal and biocompatibility characteristics of dialysis membranes according to their composition (that is, polymeric makeup) and structure. In this regard, the manner in which membrane biocompatibility interacts with flux is highlighted.

An economic survey of the emerging tissue engineering industry.

The contemporary scope of worldwide tissue engineering research and development was estimated by totaling the relevant annual spending and other economic parameters of firms involved the field. Operating expenses allocated to tissue engineering in 1997 exceed $450 million and fund the activities of nearly 2,500 scientists and support personnel. Growth rate is 22.5% per annum. Most activity is centered in the United States. Government spending in this field represents <10% of the total. The aggregate capital value of start-ups that have gone public was approximately $1.7 billion as of January 1, 1998; total capital value of all firms and business units in the field was estimated to be roughly $3.5 billion. The level of investment and valuation represents a remarkable act of faith in the future of a technology yet to produce its first significant revenue-generating product.

Plasma therapy at Klinikum Grosshadern: a 15-year retrospective.

Immediately after the availability of highly permeable membranes in 1979, membrane plasma separation was introduced as a mode of extracorporeal blood purification by the nephrology group at Klinikum Grosshadern of the Ludwig Maximilians University of Munich (F.R.G.). The new therapy was applied primarily in the management of immunologically mediated renal and extrarenal disorders as well as in paraproteinemias. We also have witnessed a widespread application of this extracorporeal treatment as a last resort in otherwise refractory clinical conditions. Over the years, the group at Grosshadern has contributed to the development, as well as to the laboratory and clinical testing, of new plasma separation membranes, simplified plasmapheresis formats (e.g., spontaneous membrane plasma separation), and several plasma fractionation procedures (e.g., cascade filtration, adsorption). Whenever indicated and possible, plasma fractionation procedures, rather than unselective plasma exchange, are performed in an appropriate clinical situation.

Transport characterization of membranes for immunoisolation.

This study relates to the diffusive transport characterization of hollow fibre membranes used in implantable bio-hybrid organs and other immunoisolatory devices. Techniques were developed to accurately determine the mass transfer coefficients for diffusing species in the 10(2)-10(5) MW range, validated and then used to study one membrane type known to effectively immunoisolate both allografts and xenografts in vivo. Low-molecular-weight diffusing markers included glucose, vitamin B12 and cytochrome C; higher-molecular-weight molecules were bovine serum albumin, immunoglobulin G, apoferritin and a range of fluorescein-tagged dextrans. Overall and fractional mass transfer coefficients through the hollow fibres were determined using a resistance-in-series model for transport. A flowing dialysis-type apparatus was used for the small-molecular-weight diffusants, whereas a static diffusion chamber was used for large-molecular-weight markers. For diffusion measurements of small-molecular-weight solutes, convective artefacts were minimized and the effect of boundary layers on both sides of the membrane were accounted for in the model. In measuring diffusion coefficients of large-molecular-weight species, boundary layer effects were shown to be negligible. Results showed that for small-molecular-weight species (< 13,000 MW) the diffusion coefficient in the membrane was reduced relative to diffusion in water by two to four times. The diffusion rate of large-molecular-weight species was hindered by several thousand-fold over their rate of diffusion in water.

Product development in tissue engineering.

Tissue engineering may be defined as the application of the principles and techniques of biomedical engineering to products and processes involving living cells. As such it is located at the confluence of traditional medical device technology, molecular pharmacology, and cell biology. Effective function at this interface has proven both elusive and critical in tissue engineering research and is likely to remain a determinant of success or failure as products move from research through development and into clinical practice. As a further challenge, regulatory processes, traditions, and approval pathways are rather different for medical devices than for Pharmaceuticals and biologies, and commercialization of hybrid products will require knowledge and expertise in both areas. This review compares and contrasts the development cycle for medical devices and pharmaceutical products and highlights the major development issues facing emerging tissue engineering products.

Recent progress in immunoisolated cell therapy.

Biohybrid implants represent a new class of medical device in which living cells, supported in a hydrogel matrix, and surrounded by a semipermiable membrane, produce and deliver therapeutic reagents to specific sites within a host. First proposed in the mid-1970s for diabetes, this treatment modality has progressed rapidly in the past four years and is now being investigated not just for endocrine disorders but also for alleviation of chronic pain, treatment of neurodegenerative disorders, and delivery of neurotrophic factors to sites within the blood brain barrier, and as a practical alternative to conventional ex vivo.

The influence of dialysis treatment modality on the decline of remaining renal function.

A retrospective investigation was undertaken in which the rate of decline of residual renal function (RRF), estimated from creatinine clearance, was compared in 55 continuous ambulatory peritoneal dialysis (CAPD) and 57 hemodialysis (HD) patients for whom a minimum of four (mean of 7.6) well-spaced historic measurements of residual clearance were available. Because of the intrinsic variability that attends such data, specialized nonlinear, growth curve statistical methods were employed. Residual function was found to decline exponentially after the onset of therapy in both cohorts. The rate of decline in the HD group was twice that of the CAPD group (5.8% +/- 0.4% per month for HD vs 2.9% +/- 0.3% per month for CAPD; difference significant at p less than 0.0001). This difference remained highly significant (p less than 0.01) when corrected for other potential risk factors such as age, gender, hypertensive status, and use of angiotensin converting enzyme inhibitors in patients with diabetic or other forms of glomerular nephropathy. Differences between cohorts were not significant for patients with other diagnoses (p greater than 0.1) although the size of some of these subsets was very small. The physiologic mechanism for the more rapid fall-off of RRF on HD remains speculative, but could be related to renal ischemia secondary to intratreatment hypovolemia and/or to nephrotoxic effects of the inflammatory mediators of extracorporeal circulation.