2.1.

Wellman Center for Photomedicine

The Wellman Center for Photomedicine (WCP) is one of the five thematic research centers located in Mass General Hospital, the academic hospital of Harvard Medical School. Founded in 1976 by Harvard Dermatology Professor John A. Parrish MD, WCP occupies today 38,000 sq. ft, and has 14 core faculty, 12 affiliated faculty, and a total of more than 250 professors, staff, and students working in a multidisciplinary clinical translational environment. Its name honors Arthur Wellman, a philanthropist whose wife was successfully treated for disabling psoriasis with oral psoralen activated by UV-A radiation (PUVA), a new discovery at the time by Dr. Parrish whose early work focused on human skin photobiology and novel treatments for skin disease (Fig. 1). Dr. Parrish then recruited physicists, engineers, pathologists, immunologists and cell biologists to work together investigating the fundamentals of light–tissue interactions. The original motivation was to explain and improve treatments that clinical research had already shown to be effective.

Fig. 1

Founding WCP director Dr. John Parrish (left), meets with philanthropists Arthur (center) and Gullan Wellman (front right) in 1982. Also present are Thomas B. Fitzpatrick, Chair of the Department of Dermatology, Harvard Medical School and MGH (second from left) and Nicolas W. Thorndike, Chairman of MGH Board (second row, right).

While this ambitious goal was partially achieved, the effort led to a much wider impact. WCP multidisciplinary research teams developed a passion for understanding and manipulating the rich portfolio of molecular changes caused by optical irradiation of living tissues. Fascinating photochemical, thermal, and physical reactions were explored and documented in detail. Simultaneously, laser, fiber optic, computational, imaging, and molecular biological technologies were rapidly advancing. In 2004, WCP formally embraced the power of multidisciplinary research. In contrast to traditional medical departments based mainly on organ systems, WCP became a nondepartmental MGH Thematic Center, with Dr. Rox Anderson MD as its new director.

What started as a skin laboratory evolved to be a center contributing high-impact solutions for “the skin and everything in it.” Laser lithotripsy was developed and launched commercially for removing urinary stones.⁴ Other projects such as laser angioplasty met with scientific success but practical failure. The concept of selective photothermolysis was introduced,⁵ leading to many novel laser treatments for skin, eye, and laryngeal disorders. For the first time, biomedical needs spearheaded the invention of new laser technologies. Fractional laser treatment was invented to stimulate skin remodeling, and is fast becoming a major treatment to normalize scars. The early interest in light-activated drugs evolved into creative, versatile examples of photodynamic therapy (PDT). Benzoporphyrin derivative, a drug initially intended for cancer treatment, was repurposed to become the first approved treatment for retinal macular degeneration.⁶ Studies of tissue optics including early mathematical models of diffuse radiation transfer were produced, which set the stage for optical diagnostics. The first laser confocal microscope for human use was invented and commercialized,⁷ now in clinical use. Optical diagnostics became a sophisticated and diverse field unto itself. The speed, resolution, and capabilities of OCT, which was invented at MIT almost 30 years ago for retinal imaging, were greatly advanced by WCP innovations.⁸ Unprecedented 3-D tissue imaging became possible through needles, cardiac catheters, swallowed microscopes, and other devices. In addition to the stand-alone optical diagnostic devices in many medical specialties, we are witnessing now their integration with conventional medical imaging, their use for real-time guidance of surgical and other procedures, and low-cost simplified versions applicable to solving global health problems.

The fundamental strength of WCP has always been high-quality scientific inquiry. For example, a basic understanding of photothermal processes is what enabled a host of new laser therapies. Tissue optics and in vivo spectroscopy enabled optical diagnostics. Photochemistry enabled photodynamic therapies, including some surprising capabilities now in development. New themes are emerging at WCP, sometimes beyond the general theme of photomedicine. For example, the popular use of controlled cryotherapy for selective removal of unwanted body fat is a WCP innovation.

2.2.

Beckman Laser Institute and Medical Clinic

Around the same time that Dr. Parrish was working on human skin photobiology, Dr. Michael W. Berns, PhD, was a professor of cell biology at the University of California, Irvine (UCI). In 1979, Dr. Berns invited Dr. Arnold O. Beckman, PhD, an inventor-businessman-philanthropist and founder of Beckman Instruments, Inc. to an “open house” in the Berns lab. At that time, Dr. Berns had established the first NIH P41 National Biotechnology Research Resource Center for laser microbeams [the Laser Microbeam Program (LAMP)], a new technology for cellular microsurgery he had pioneered as a Cornell University graduate student.⁹ Lasers and their potential applications in biology and medicine captured the imagination of Dr. Beckman and he worked with Dr. Berns to form the Beckman Laser Institute and Medical Clinic (BLI) in 1982 (Fig. 2). Together they created a BLI nonprofit foundation to raise money and build a free-standing building on the UCI campus. This early successful example of a public–private partnership led to the original BLI structure that opened in 1986. In 2003, Dr. Bruce Tromberg, PhD, was appointed BLI director and Dr. J. Stuart Nelson, MD, medical director. BLI was designated as a campuswide “special research program” in 2006 but maintains its original Medical School affiliation as a division in the Department of Surgery.

Fig. 2

In 1982 Dr. Arnold O. Beckman (left) presented Dr. Michael W. Berns, founding BLI director, with the first check to establish the Beckman Laser Institute at UC Irvine.

Although the terminology did not exist at the time, this was the first dedicated translational facility constructed specifically for advancing basic science, technology development, and clinical translation of lasers and optics, all under one roof. Several unique design features that were decades ahead of their time characterized the building, including open shared spaces; shared resources for cell biology, biochemistry, histopathology, animal models, and image processing; and a dedicated laser clinic and operating room. In addition, a fiber optic network was built throughout the BLI clinic for delivering light from massive, water- and power-hungry lasers, the standard of the day, to any treatment room in the clinic. Although UCI and Lasers were only 17 and 22 years old, respectively, when BLI was established, Dr. Beckman had the foresight to invest significant resources in a young professor, an unproven university, and an emerging technology.

The goal of the 1979 NIH LAMP facility was to develop tools for selectively altering small regions of living cells in order to study cell and organelle function. As core technologies continued to develop, new applications of the laser microbeam evolved, particularly in the area of gradient force optical trapping, chromosome microdissection, laser-induced gene transfection, and nonlinear laser microbeams.¹⁰ Although rooted in basic science, the perceived clinical and commercial potential of LAMP technologies inspired Dr. Beckman and Dr. Berns to establish the BLI, a crucial step that accelerated the clinical translation of lasers and optics.

Today the BLI is a 37,000 sq.-ft free-standing facility with 17 faculty and more than 200 professors, staff, and students from more than 10 science, engineering, and clinical departments on the UC Irvine campus. Clinical applications emerged within BLI in the late 1980s, particularly in the areas of PDT for cancer and dynamic cooling technology for cutaneous laser surgery.¹¹ Several important new technologies, biomedical applications, and clinical studies appeared during subsequent years, including laser microbeam assisted in vitro fertilization technologies,¹⁰ Doppler OCT for imaging blood flow,¹² diffuse optical methods for imaging perfusion and metabolism in thick tissues,¹³ and multimodality endoscopic tomographies.¹⁴ Virtual photonics technologies also emerged, an effort entirely dedicated to biophotonics modeling and computation for simulating and visualizing light propagation in biological tissues.

2.3.

Medical Laser Center Lübeck

In Europe in 1975 Dr. Franz Hillenkamp PhD, a young biomedical engineer who led the Laboratory for Coherent Optics at the “Gesellschaft für Strahlen- und Umweltforschung,” a National Laboratory for Radiation and Environmental Research in Munich, Germany, introduced a Medical Laser Applications Laboratory. This center provided standardized laser- and optical delivery-technology together with extended animal facilities for application oriented in vitro and in vivo studies in laser medicine. Medical scientists from ophthalmology, gastroenterology, urology, neurosurgery, and oral surgery performed studies in the areas of photocoagulation and photodisruption in ophthalmology, laser-induced hemostasis in gastric ulcers, laser therapy of bladder tumors, and laser bone surgery. Dr. Alfons Hofstetter MD, the urologist in this research group, left Munich and became Chairman of Urology at the University of Lübeck in 1984. Much like Dr. Parrish and Dr. Berns whose early research seeded the growth of larger centers, Dr. Hofstetter’s work initiated the foundation of the Medical Laser Center Lübeck (MLL—formal “Medizinisches Laserzentrum Lübeck GmbH”). The MLL, funded by the German state of Schleswig-Holstein as a separate, but university-associated R&D Institution at the University of Lübeck, opened in 1986.

The intention of MLL from the very beginning was to introduce, launch, and establish laser technologies in medicine. Core expertise in high-power IR-lasers, short- and ultra-short pulse-lasers, miniaturized solid-state lasers, etc. was leveraged by interdisciplinary and transinstitutional collaborations between research institutions, industry, and hospitals. In order to facilitate translation of research to clinical practice, the MLL was founded as a nonprofit limited liability company (GmbH) with seven associates, two universities including the leading state hospital, four biomedical companies, and the Hanseatic city of Lübeck. Physicists, a biologist, engineers, and physicians were hired and a research building was constructed together with a guesthouse for collaborators and participants of conferences and training courses. Application-oriented R&D-projects in urology (lithotripsy), tumor therapy (PDT) quickly emerged.

In 1991, Dr. Reginald Birngruber PhD, MD became the Chief Executive Officer (CEO) and Chief Research Officer (CRO) of the MLL and research initiatives in ophthalmology (picosecond photodisruption, PDT, microphotocoagulation) and cardiovascular laser therapy (laser angioplasty) were added, always in close collaboration with clinicians and various laser companies. Understanding mechanisms of light–tissue interaction and photothermal tissue effects became crucial research activities that helped drive the development of novel and economically successful technologies. Examples include, mathematical modeling of temperature profiles, thermal denaturation kinetics,¹⁵ and nonlinear processes in pulsed laser tissue ablation.¹⁶ New laser systems like the Alexandrite solid-state laser and high-power picosecond lasers were modified and adapted to solve specific clinical problems. A mutual collaboration with the Wellman Center for Photomedicine in Boston resulted in the invention and development of new medical laser applications, including carrier-mediated PDT to make age-related macula degeneration (AMD) a treatable disease for the first time¹⁷ and selective retina therapy for precise treatments of various early stage retinal diseases.¹⁸ Several medical laser devices were commercialized in collaboration with MLL’s partners, for example, the first feedback controlled laser-lithotriptor Lithognost,¹⁹ several PDT laser devices for ophthalmology, and a miniaturized handheld IR-laser scalpel for trabeculectomy.

In 2005, the Institute of Biomedical Optics (BMO) was formed out of the MLL-research teams and became part of the University of Lübeck. BMO was created to offer new courses in biomedical optics, photonics, optical imaging and laser medicine to educate and prepare the next generation for emerging technologies in optical life sciences. BMO, now an academic institution, hosts undergraduate and graduate students and can conduct research in all aspects of optics in medicine and biology, supported by more traditional state and federal funding. MLL kept its status as a nonprofit R&D company financially independent and supported solely by project funds derived from clinical, translational and applied research in collaboration with clinical and industrial partners (Fig. 3). After Dr. Birngruber retired in 2010, Dr. Alfred Vogel PhD became the Director of the BMO, and Dr. Ralf Brinkmann PhD took over MLL as its CEO in 2011.

Fig. 3

Dr. Reginald Birngruber (center), MLL founding CEO, meets with current CEO Ralf Brinkmann (left) and Annette Schavan (right front), German Minister of Research and Education, in 2006.

Today, MLL and BMO have 10 faculty and more than 80 professors, staff, and students working in the interdisciplinary field of biophotonics. Therapeutic laser applications are still the strongest MLL focus area. Activities in imaging and in vivo diagnostics, metrology, laser material processing and prototype development, and management of clinical studies continue to expand. A unique feature of MLL as a limited liability company is that it can legally register prototypes according to the European medical product law and perform proof-of-concept clinical trials. This strong partnership between a university institute, a university hospital, and a highly flexible nonprofit R&D company, sharing infrastructure and personnel, but being formally independent, has been proven highly successful. Importantly, the MLL with its own lean administrative structure and low overhead can act quickly and adapt to short-term industrial tasks, but also serve as a reliable partner in long-term public funded programs.