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The Pursuit of Noninvasive Glucose: “Hunting the Deceitful Turkey” By John L. Smith Seventh Edition: Revised and Expanded Parts Copyright 2020 by John L. Smith i Preface to the Seventh Edition The hopeful prediction that the sixth edition might have been the final update this subject needed was incorrect, and while much of the new effort has indeed been directed toward continuous “wearable” glucose monitoring, there has been no decrease in the number of new attempts to end this pursuit. The arrival of the Coronavirus in early 2020 will certainly reduce the number of groups surviving for this pursuit, as it will affect many other areas of our lives. The 6th edition premiered a “NEW” index with new or revised entries; that version has been combined with the earlier index, and replaced with one composed of the new entries in this edition. Another attempt to identify new content has been made by entering it in colored type (simple editing corrections will not be so noted). Index entries for new content will also appear in red type. Time will tell if this is more helpful than annoying for both the author and the reader. A growing trend has been the increase in attempts to mine the pulse wave (see “PPG” below) for both glucose and noninvasive blood pressure information—indeed, several groups appear to have migrated primarily to the pursuit of the latter after not succeeding with the former, but to date, results have been no more promising. Emphasis on the new, large players in the broader field (Apple, Google, Samsung, and Microsoft) has continued, and even though the furor surrounding the Last Big Event (Google’s touted but ill-fated contact lens) has abated, others have leaped into that void. “Will the Noninvasive Glucose Monitoring Revolution Ever Arrive?”1 1 A note about Internet links. At the risk of reading like a Wikipedia entry, the first appearance of companies, groups, and systems that were current or have persistent links as of this writing in 2018 will be provided with links that mostly survive into the .pdf edition you are reading. Many of these groups are ephemeral, and some don’t survive beyond a single initial press release, so please accept the reality that quite of few of these will be dead ends. Any that had already disappeared by the time of writing have been deleted. ii To aid those still determined to try, my guidance of the disciplines where knowledge for a reasonable chance at success is required is repeated: • The engineering disciplines related to your primary technology, e.g., optics, electronics, software, mechanical engineering, etc. • Biochemistry, especially knowledge of the glucose molecule and its relation to the chosen field of technology. • Physiology, especially the distribution of glucose in fluids and tissue. • Metabolism, especially glucose sources and sinks. • Diabetes, especially aspects of the disease that will affect your technology—the more understanding of endocrinology, the better. • The history of noninvasive investigations, especially in your technology field— what didn’t work and why. • The regulatory requirements for a diagnostic device, and the evolving structure of the market for existing devices. The most optimistic estimates of earlier investments indicate the need to spend a minimum of five years and raise 25-30 million dollars to be ready to place a device on the market. No matter how rapidly the market would embrace a new noninvasive device, time and money that must be allocated for manufacturing scale-up, establishing a distribution network, and educating both patients, providers, and insurers about the new system, which will require additional resources and funding. Business plans that ignore these realities may seem attractive, but will not withstand the scrutiny of experienced investors. Copyright Notice Anyone can view, copy, and reproduce any part of this work for non- commercial purposes as described in the fair use clause of United States Copyright Law. Reproduction of any copyrighted part of this work in any form for commercial purposes is strictly forbidden.1 1 Glenn Elert, who will probably be writing the wonderfully instructive and readable Physics Hypertextbook as long as he is alive, taught me to add this statement. He also suggested including the Latin phrase Opus in profectus: “work in progress.” iii Foreword This is a compilation of experiences and investigations, now stretched over 35 years and born of a combination of scientific curiosity, dedication to people affected by a chronic, life-threatening disease, and dogged determination to find a solution to the most difficult technical challenge encountered in a long career. It is not, perhaps, as difficult or fraught with problems as realizing time travel or finding the final “grand unifying theory” of physics1, but it is the more tantalizing because it seemed for decades that the solution was always “just around the corner,” or at most, “just over the horizon.” Although much of the content is now quite dated, it is included for new readers as a historical perspective of the duration of this pursuit. I participated in development and evaluation of many of the older technologies (and even a few of the new ones) described here while employed at several companies directly or peripherally involved in glucose measurement, and I have consulted for the inventors or investors of many others. In the text, I will describe many of the technologies, their capabilities and (especially) their limitations for measuring glucose. I will articulate three very important “Laws of Noninvasive2 Glucose” (one with several subsections), and list tests which can be applied to spectroscopic and other techniques. Much of the description is technical, since it is the subtle technical failings of the approaches that generally lead to their demise. Nontechnical readers should still try to read through these—the conclusions are valid, some of the reasoning may be helpful, and there is certainly value in them as cautionary tales. Where companies have made a splash, or serve to illustrate the behaviors that were exhibited by many of those in this field, they will be described in some detail. In other cases, simple lists of the investigators will serve to illustrate how many times a similar approach has been attempted. 1 The long-sought system for reconciling General Relativity and quantum mechanics that caused Einstein so much heartache in his later years. 2 Although I will try to follow the punctuation rule that short prefixes such as “un-” and “non-” are generally unhyphenated unless confusing, the term appears equally often as “non-invasive,” and this can complicate searches, depending on the sophistication of the search process used. When searching patents, for instance, both forms must be included for most search engines. iv Although I do not (yet) have a diagnosis of diabetes, it has reached epidemic proportions in this country, and is, as the standard of living rises elsewhere, increasingly felt more equally around the world. After spending years devising instruments that measure blood glucose and participating in the explosive growth of the home blood-glucose monitoring industry in the 1990s, the need for a device that would allow people to measure their glucose without pain or trauma is as clear to me as it is to people who would use it. As will be described here, it is not through lack of effort, creativity, entrepreneurialism, or funding that no solution has yet been found. Nor is it due to a deficiency of craftiness, manipulation or chicanery. The immense market size (still estimated worldwide at perhaps ten billion dollars in 2020), together with the pent-up demand by millions of patients, will promise a financial success for the organization that finally solves this problem. A device of acceptable accuracy, of reasonable size, and at reasonable cost, would still be a medical and commercial success, but see the cautions that follow below. For all these reasons, hope springs eternal in the hearts of scientists, entrepreneurs, opportunists and charlatans alike. One of the most disturbing aspects of this field has been perennial announcements by fledgling companies that the problem has been solved, and that people with diabetes will no longer have to stick their fingers.1 These have been premature and, almost without exception were meant to generate “hype” in order to increase awareness of a company that is trying to raise money, but equally frequently, they raise false hopes in people who need the product. News media have never been able to resist reporting these “end-of- finger stick-testing” stories, and they have a fresh audience each year, as hundreds of thousands of people are newly diagnosed with diabetes. Each group gradually tires of the premature announcements and develops a level of cynicism. As I will detail, no successful device has yet been developed, and any real prospects for one remain in the future. Another cause for concern in this field is that, in all too many cases, the same technology has been picked up and investigated after others have determined that it will not succeed. Because there has been little previous accounting of these multiply- 1 It brings to mind the continued appearance of articles in popular science magazines about the soon-to-be affordable car that converts into an airplane to fly swiftly over traffic jams. v investigated approaches, investigators and investors alike have no guideposts to direct them. This book will be of interest primarily to those who have participated in this enduring quest, those who seek to invest in the field, or perhaps to those who have heard too many false promises about the “coming noninvasive revolution.” Many of the illustrations, (and no small amount of the information presented here) have been “borrowed” from the experiences and websites of others who have preceded me in this field, most notably David Mendosa, who maintained for many years an accurate list of participants in the noninvasive glucose field while chronicling the history of glucose monitoring.

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