HYPOTHETICAL ETIOLOGY AND COMPETITIVE ASSESSMENT OF TERAHERTZ LIGHT INDUCED RHYTIDE IMPROVEMENT BY: JOSEPH TSUN DAW TAN Submitted in partial fulfillment of the requirements For the degree of Master of Science Thesis Advisor: Dr. Christopher Cullis Department of Biology CASE WESTERN RESERVE UNIVERSITY May 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ___________________________JOSEPH TSUN DAW TAN_________________________ candidate for the Entrepreneurial Biology Masters degree*. (signed) ________________________DR. ROBIN SNYDER_________________________ (chair of the committee) ______________________DR. CHRISTOPHER CULLIS______________________ _________________________DR. JEAN WELTER__________________________ ________________________DR. GERALD MEARINI________________________ _____________________________________________________________________ (date) ______1/20/2012______ * We also certify that written approval has been obtained for any proprietary material contained therein. 2 Table of Contents List of Tables 5 Acknowledgements 6 Abstract 7 Introduction 8 1 Characterizing the need 9 1.1 Market overview and geographical perspectives 9 1.2 Market segmentation : clarifying the rhytide improvement market 10 1.3 Identifying the central job to be done : bolstering self-concept 10 2 Current approaches and their limitations 11 2.1 Relevant anatomy and composition of skin 12 2.2 Rhytide formation : aging and photoaging 13 2.3 Primer on infrared interaction with skin 15 2.4 EMR-based rhytide improvement techniques and etiology 18 2.4.1 Ablative skin resurfacing 19 2.4.2 Non-ablative approaches 20 2.4.3 Fractional photothermolysis 23 2.4.4 Radiofrequency (RF) stimulation 23 2.5 Other interventional techniques and their mechanisms 24 2.5.1 Rhytidectomy 25 2.5.2 Topicals 25 2.5.3 Botulinum toxin 25 2.5.4 Soft tissue fillers 26 3 2.6 Market and technical analysis of leaders in aesthetic lasers 26 3 Hypothetical mechanisms of terahertz rhytide improvement 28 3.1 Existing evidence of THz exposure on biological systems 28 3.1.1 Penetration depth on skin and water 29 3.1.2 Primary chromophore – hydrogen bond resonance 30 3.1.3 Membrane effects 31 3.1.4 Biophotomodulatory evidence 31 3.2 Finding THz’s unique value proposition in rhytide improvement 34 4 Testable hypothesis to generate proof of concept and safety data 35 4.1 Available equipment for THz delivery 36 4.2 Discussion of experimental models 37 4.3 Testable hypothesis and planned experimentation 39 4.3.1 Hypothesis 1: Genotoxicity 39 4.3.2 Hypothesis 2: Thermal stress and biophotomodulation 40 4.3.3 Hypothesis 3: Membrane effects/potentiation of topicals 41 5 Conclusion 43 Bibliography 44 4 List of Tables Table 1. Summary and comparison of various categories of EMR-based skin 19 resurfacing approaches ranked in order of clinical invasiveness. Table 2. Revenue and product comparison of top six aesthetic laser companies 26 5 Acknowledgements First and foremost, I would like to thank the members of my thesis committee, Drs. Christopher Cullis, Jean Welter, and Gerald Mearini for taking the time to contribute their respective expertise towards this multidisciplinary project. Without Dr. Cullis’s vision for the department that enabled me to transition into this new career path, Dr. Mearini’s providing me the forum, opportunity and mentorship to pursue this line of research, and Dr. Welter’s patient support in helping me gain confidence in my argument and clarify my scope, I would not be here today. I would like to thank my other mentors who have made an impact on me during my time at Case Western Reserve University: Dr. Hillel Chiel, Dr. Mary Davis, Ed Caner, Bruce Terry and my CGA representative, Dr. Robin Snyder. At every critical juncture of a tribulation that I thought I could not overcome, they provided me with support and perspective outside of the expectations of their position. I hope to be able to do for others as they have done for me, and will always reflect fondly on this institution that I proudly call my alma mater. I would like to thank my family in both generational directions, and without genetic boundary. They are my reason for living, and I hope to be there for them in their time of need as they have been there for me. Finally, to my darling wife, thank you for loving me when I felt like nothing. If that is not true love, I do not know what is. May all who read this stay young at heart. 6 Hypothetical Etiology and Competitive Assessment of Terahertz Light Induced Rhytide Improvement Abstract by JOSEPH TSUN DAW TAN Aesthetic lasers are a billion dollar industry that continues to grow at a CAGR of 9.0%. The age-resisting rhytide improvement market is driven by consumer consumption of lower-risk, minimal-downtime, and highly effective approaches. The clinical and market success of novel combination techniques has already prompted consolidation in a highly fragmented market, suggesting that continued innovation in this space could yield great dividends. The advent of new technologies that unlock the last unexploited band of electromagnetic radiation offers the prospect of new combinatorial value in a space still ripe for consolidation. Existing evidence suggests that THz exposure on skin can achieve dermal impact, achieve non-genotoxic membrane permeability increases and preferentially initiate production of regeneration recruiting molecules via non-thermal biophotomodulation. Further work is proposed and must be performed to clarify the best mode to deliver the maximum beneficial bioeffects from THz exposure. 7 Introduction Our faces are our social passports to the world. Every day, our face is a part of our personal brand, an evolutionarily enforced schema that helps others remember who we are and the physical construct that connects us to the rest of our personhood. But as we age, this external construct so intrinsically tied to self-concept inevitably changes, so it is no surprise that the cosmetic anti-aging and vanity industry is at least a $17 billion industry1, spanning multiple industry segments and occupying a significant portion of discretionary income. Thus, it is not difficult to understand the driver of these markets, but actually delivering this value to the consumer, reversing the effects of time and biology, is not as simple, and is the holy grail of the vanity industry. For this study, we will focus on one subset of this market: rhytide improvement, colloquially referred to as wrinkle smoothing or skin rejuvenation, and more specifically, solutions via electromagnetic radiation (EMR). We will characterize the need, review the underlying etiology behind rhytides and current approaches, and introduce the scientific underpinnings of a novel EMR-based approach that utilizes the last unexploited bandwidth of EMR, terahertz light (THz). After reviewing the current state of understanding of THz phenomenology, we will suggest several product strategies after defining areas of unique value proposition, and provide a technical roadmap of the next steps to reaching market. 8 1 Characterizing the need 1.1 Market overview and geographical perspectives According to market research firm Frost & Sullivan, in 2005, the aesthetic lasers market had revenues of $589.2 million with a projected compound annual growth rate (CAGR) of 9.0% based on market data from 2002-2005. Today, this represents an approximately $1 billion market that is highly diversified in approach and market participation.2 Frost & Sullivan correctly predicted the high potential for market consolidation when in 2009, Syneron, making increasing gains on the market with the newest combination technologies, merged with Candela, the incumbent market leader, making Syneron the largest aesthetic laser company in the world.3 Differing regulatory hurdles necessary to market in North America, Europe, and Asia have made geographic analyses of cosmetic medical products an important consideration. Past history has shown that North American and Asia/Pacific (APAC) regions delay regulatory approval until European markets generate sufficient safety evidence, demonstrating European markets as a testing ground for worldwide aesthetic laser markets. However, while Europe is a great indicator of which technologies perform best, the APAC region is the one with the largest growth potential with a project CAGR of 17.6%.4 Much of this growth is attributed to the rise in discretionary income in China, which only contributed 10% of the APAC market. While in 2005, North America held 47% of the world market share, Asia is reportedly the market leader in spite of tightening regulatory control in the region.5 9 1.2 Market segmention : clarifying the rhytide improvement market While laser hair removal was the largest single application of aesthetic lasers, skin rejuvenation, resurfacing and tightening as a sector comprised 56.5% of the aesthetic laser applications market.6 Because of the ubiquity of aging wrinkles, rhytide improvement is the predominant application within this segment, which also includes treatment of more narrow afflictions of acne scars, vascular and pigmented lesions. Where there were five aesthetic laser companies in 2005 that claimed 60.9% of market share, in the skin rejuvenation market, the top five participants in the skin rejuvenation space claimed only 39.9% of the market share, demonstrating the multitude of participants and techniques in that space. We will explore these techniques and their etiology in section 2. 1.3 Identifying the central