Hyperspectral Imaging: Shedding New Light on Wound Healing
September 12, 2012
David Allen takes readings using a NIST standard reflectance diffuser prior to scanning a wound area on an anesthetized pig. Illumination comes from the broadband lights on the hyperspectral camera.Clinicians who treat severe wounds may soon have powerful new diagnostic tools in the form of hyperspectral imaging (HSI) devices, calibrated to new NIST standard reference spectra, which will provide unprecedented perspective on the physiology of tissue injury and healing.
For example, a key factor in wound healing is the amount of oxygen in the tissue – a function of the gradual re-establishment of small blood vessels severed in the injury. At present, that process can’t be assessed without biopsies or transcutaneous techniques limited to a single point.
Many physicians would prefer to use completely non-invasive HSI methods that have become available in the past decade to measure perfusion and other variables that determine outcomes over large areas.
“The potential of HSI is there, its utility has been demonstrated, and people are aware of it,” says David Allen of PML’s Sensor Science Division. “But HSI isn’t being used routinely in the clinic yet. Why? One big reason is that standards aren’t in place. Individual researchers doing their own experiments show positive results. But when you start comparing an instrument in one lab to an instrument in another, the data are typically inconsistent.” Factors limiting repeatable results include biological variability (variations in skin pigmentation, tissue density, lipid content, and blood volume changes), and sensor variability related to calibration and best practices in the measurement protocol. While the biological variability is beyond researchers’ control, the sensor variability can be minimized.
In pursuit of that goal, Allen and colleagues have now produced the first prototype “digital tissue phantoms” derived from bench-top simulations and in-vivo wound imaging. Phantoms are objects that are deemed reasonably equivalent proxies for the body or its components. The new PML digital tissue phantoms (DTPs) are a set of specific spectral signatures and images that correspond to different states of hemoglobin oxygenation due to ischemia (inadequate blood flow) which ultimately result in cell death due to oxygen deprivation.
Ultimately, more extensive and clinically validated versions of the phantoms can be used to calibrate spectral imaging devices of various kinds. Those devices will be able to detect the telltale spectral evidence of ischemia, revascularization, assorted pathologies, and other conditions suggestive of tissue viability at a wound site, on a microvascular scale – even during surgery.
But in order for that to happen, there must be a well-characterized and clinically validated correspondence between particular spectral signature and particular tissue conditions. Allen and scientists from Ron Xu’s group at the Ohio State University (OSU) Biomedical Engineering Dept, recently took a major step in that direction by imaging carefully manipulated ischemic wounds in an anesthetized pig. “This is the first time anybody has looked at a porcine skin flap animal model hyperspectrally,” Allen says. “The collection of the hyperspectral data for use as a reference is a small but very significant milestone.”
On two areas of the animal’s back, flaps of skin were raised, silicone-plastic sheets were placed beneath the skin to inhibit reperfusion, and the incisions were closed. On adjacent areas were a skin flap without plastic sheets and an untreated control area. Allen scanned all the areas with a highly sensitive hyperspectral imager, using illumination from a standard broadband light source. In this work, a typical scan encompassed 240 different wavelengths, spaced about 2 nm apart, ranging from 400 nm to 880 nm. As a reflectance reference, each image also included light from a NIST-traceable standard diffuser. Readings at each wavelength were then stacked into “data cubes” for each scanned position.
A hyperspectral line camera with four broadband light sources acquires images with the lens at center. A typical scan captures images at hundreds of discrete wavelengths that differ by as little as 2 nanometers.
“We really nailed it,” Allen says. “We found that we can reproduce the tissue spectrum – including the oxygenation level of hemoglobin – to within one standard deviation, well within the natural variability of the tissue.”
The work is the latest development in an initiative that began about five years ago at the behest of former NIST Director William Jeffrey. “He met some people in the field, biomedical engineers and researchers who had begun doing this kind of work, and asked how NIST could help,” Allen says. “This community was excited to partner with NIST in working towards advancing this technology.”
Soon thereafter, Allen’s group applied for, and received, competitive NIST funding to develop standards for the nascent field. The principle investigators included are Toni Litorja, Jeeseong Hwang, Antonio Possolo, Eric Shirley and David Allen. One part of that award supported use of a PML device called the hyperspectral image projector (HIP), developed by Joe Rice and others at NIST, which reproduces complex spectral-spatial images very accurately by precision control of digital micromirror devices. (See Figure 3.)
When medically significant hyperspectral scenes are projected, they are referred to as digital tissue phantoms. They allow realistic medical scenes to be produced repeatedly without the variability and expense that would occur if the medical procedure was repeated every time that a hyperspectral image was evaluated. Already Allen’s group has been able to generate HIP-projectable spectral signatures that correspond to different levels of oxygenation in tissue.
Currently, accumulating the data for DTPs is a time-consuming process: Each scan takes from tens of seconds to a minute or more. “That’s the state of the technology right now,” Allen says. “But in the future, we’ll have ‘snapshot’ hyperspectral scans for real-time imaging, including video. Eventually, we want to get to the point at which you can see the blood perfusing through the tissue.”
As more measurements accumulate, Allen says “we’ll be able to collect a standard set of these data cubes that are well known and well characterized, and make them available as a kind of library with an indefinite shelf life. Users could then come here with their instruments, view our projections, and see if they get the same results. We have done the same sort of thing in the past, providing ‘ground truth’ data for satellite sensors that measure ocean color.” Because the spectra are in digital form, they can be reproduced indefinitely and identically.
So far, Allen’s group has had productive collaborations with OSU and at the University of Texas (UT) at Southwestern Medical Center, where scientists continue to make HSI measurements of various surgical procedures. More will join the effort. “We need to repeat the procedure in different labs using different approaches,” Allen says, using both in-vivo sources and bench-top apparatus that can be tuned to simulate the reflectance signature of different organs at different oxygenation levels. In the long run, these studies will make it possible for HSI to be used as a non-invasive diagnostic tool that will provide rapid results with a much greater ability to discriminate between healthy and diseased tissue. Some examples include burns, chronic wounds, and tissue margins for surgical removal of tumors. Establishing the measurement uncertainties will help guide researchers in determining the relationship between the optical measurements and what is clinically significant.
And there are other, quite different, potential uses as well. In addition to optical medical imaging, Allen is also investigating HSI’s potential in areas including environmental and defense applications such as diseases of coral reefs and the detection of hidden explosive devices. Results to date are highly promising.
A hyperspectral image such as this one, which integrates scans from 240 different wavelengths, can be used as a digital tissue phantom. The "datacube" for this image of a 15 cm X 5 cm ischemic wound combines readings from 740 individual lines and about 600 rows at 12 bits per pixel.
July 30, 2012
Dr. Jianjie Ma joins Regenerative Medicine faculty
Jianjie Ma, PhD
Jianjie Ma, PhD, is appointed as Professor in the Department of Surgery, the Karl P. Klassen Chair of Thoracic Surgery in the Department of Surgery, effective July 1, 2012, pending the approval of The Ohio State University Board of Trustees. He will also be engaged as a Davis Heart Lung Research Institute Investigator and serve on the advisory committee of the newly formed Center for Regenerative Medicine and Cell-Based Therapies in the College of Medicine.
Dr. Ma comes to Ohio State from the Robert Wood Johnson Medical School at the University of Medicine and Dentistry of New Jersey (UMDNJ) where he is a university-named professor and acting chair of the Department of Physiology and Biophysics, as well as Chief of the Division of Developmental Medicine and Research. During his time at UMDNJ, Dr. Ma founded the Graduate Program in Physiology and Integrative Biology, which is jointly sponsored by UMDNJ and Rutgers University. He served on the Scientific Advisory Board for the Cancer Institute of New Jersey. In addition, he served on several National Institutes of Health study sections and various editorial boards.
In addition to his faculty appointment with UMDNJ, Dr. Ma also founded his own company, TRIM-edicine Inc., a university spinoff biotechnology company. TRIM-edicine develops novel biopharmaceutical products for the treatment of several important unmet medical needs. One specific therapeutic protein is MG53, which targets diseases involved chronic and acute tissue damage. The other drug is ATAP, which targets apoptosis for cancer treatment.
Dr. Ma is an NIH-funded researcher, prominently and widely published on the topics of muscle physiology, aging, cardiovascular disease, cystic fibrosis, apoptosis and cancer biology. He has authored more than 130 publications and holds 10 patents. He has assembled an international team of collaborators working on translational research. His group maintains close collaboration with pharmaceutical industries for joint development efforts toward translating basic discovery into clinical application.
Dr. Ma received his bachelor’s degree in Physics from Wuhan University in China, and came to the United States through the CUSPEA (China-US Physics Examination Application) program after his undergraduate education. He was chosen to represent the Department of Physiology and Biophysics at the Graduate Student Symposium of Baylor College of Medicine, where he received his PhD in 1989. Dr. Ma went on to become an Instructor of Physiology at Rush Medical College (1989-1991) where he received postdoctoral fellowship and research grants from the Muscular Dystrophy Association, and a University Committee on Research Grant Award. Dr. Ma joined the Department of Physiology and Biophysics at Case Western Reserve University in 1992, and became a tenured Associate Professor in 1997. In 2001, he was recruited to UMDNJ as a university-named professor.
Dr. Ma has trained numerous graduate and postgraduate students, and many of them have become leaders in academia, industry, medicine and law firms. He was an established investigator for the American Heart Association (AHA) and served as advisor for many AHA postdoctoral and scientist development fellows. He is an outstanding mentor and educator, and has coordinated the teaching of both medical and graduate students at Case Western Reserve University as well as the Robert Wood Johnson Medical School. He is also actively involved in teaching and collaboration with the Chinese Academy of Sciences and universities in China.
In the News
June 26, 2012: Surgeons Perform World’s First Two Bioartificial Stem-cell Based Laryngotracheal Transplantations Using Nanofiber Solutions Scaffolds
Collaboration between Nanofiber Solutions and the Karolinska Institutet produces first synthetic laryngotracheal implants seeded with the patient’s stem cells to be successfully transplanted into human patients in Russia.
COLUMBUS, Ohio – Nanofiber Solutions, LLC, an Ohio-based developer, manufacturer and marketer of 3-D synthetic scaffolds to advance basic research, tissue engineering and regenerative medicine announced today the first and second successful transplants of its tissue engineered laryngotracheal implants seeded with cells from the patients’ bone marrow.
The surgeries were performed June 19th and 21st at the Krasnodar Regional Hospital (Russia) by Dr. Paolo Macchiarini, Professor of Regenerative Surgery at the Karolinska Institutet (Stockholm, Sweden), and colleagues. Dr. Macchiarini led an international team that included Dr. Vladimir Porhanov, head of Oncological and Thoracic Surgery at Kuban State Medical University (Russia), Dr. Jed Johnson, Nanofiber Solution’s Chief Technology Officer who created the synthetic organs, Harvard Bioscience (Boston, USA) who produced the bioreactor, and Dr. Alessandra Bianco at University of Rome, Tor Vergata, who performed mechanical testing during scaffold development.
Both patients, a 33 year-old mother from St. Petersburg and a 28 year-old man from Rostov-on-Don, were in auto accidents and suffered from a narrowing of the laryngotracheal junction for which they already had failed previous surgeries. Transplantation was the last option for the patients to have normal quality of life. Immediately following transplantation, both patients were able to speak and breathe normally.
Nanofiber Solutions, lead by Dr. Johnson, designed and built the nanofiber laryngotracheal scaffolds specifically to match the dimensions of each patient’s natural larynx and trachea, while Harvard Bioscience provided a bioreactor used to seed the scaffold with the patients’ own stem cells. Although this procedure represents the world’s first and second successful use of synthetic laryngotracheal implants, it is Nanofiber Solution’s second and third successful organ implants using their synthetic scaffolds within the last year.
Nanofiber Solutions’ scaffolds mimic the body’s physical structure and allow for a more successful seeding, growth and differentiation of stem cells. Because the cells used to regenerate the larynx and trachea were the patients’ own, doctors report there has been no rejection of the transplants and the patients are not taking immunosuppressive drugs. These are the first patients entering a clinical trial on regenerative medicine replacement, which is supported by a Megagrant of the Government of the Russian Federation, designed to invite leading worldwide scientists to Russian universities.
"We are proud to work side-by-side with Dr. Macchiarini and his team as they help define this new world of stem cell seeded synthetic transplants.” said Ross Kayuha, Nanofiber Solutions CEO.
“Tissue engineering and regenerative medicine are exciting fields that hold much promise for effective medical solutions,” continued Kayuha. “Our nanofiber scaffolds provide an innovative and ideal platform to create an array of new clinical solutions. In the hands of pioneering surgeons like Dr. Macchiarini the possibilities are almost limitless. We wish the patients continued success as they recover and hope they enjoy long, happy lives with their families.”
These historic accomplishments continue a major breakthrough in medicine, namely the ability to produce synthetic nanofiber-based organs. These surgeries are also at the forefront of two major trends in medicine today. The first is tissue engineering, or the use of artificial scaffolds in the body, and the second is regenerative medicine, including the use of a patient’s own stem cells to increase the likelihood of a scaffold’s acceptance and success.
About Nanofiber Solutions, LLC (www.nanofibersolutions.com)
Based on a technology licensed through The Ohio State University, Nanofiber Solutions is a global developer, manufacturer and marketer of 3-D products to advance life science research, tissue engineering and regenerative medicine. The company develops nanofiber-based scaffolds used in products ranging from cell culture plates for lab research to bioartificial implants for clinical use. Nanofiber Solutions sells our cell culture products worldwide through our website and distribution partners; including Sigma-Aldrich (worldwide), Neuromics (US), Akron Biotech (US), and Cambridge BioScience (UK). Nanofiber Solutions is located in the TechColumbus center in Columbus, OH.
June 8, 2012: Preeminent Tissue Engineering Team to Establish Program at Nationwide Children's Hospital. Experts to also work with OSU’s new Regenerative Medicine and Cell Based Therapies Program
Christopher Breuer, MD, Toshiharu Shinoka, MD, PhD, and their tissue engineering team will be joining the faculty of Nationwide Children’s Hospital and The Ohio State University College of Medicine this fall. Breuer and Shinoka, currently at Yale University, were the first in the world to tissue engineer blood vessels and implant them in human infants for repair of congenital heart defects. They currently have US Food and Drug Administration (FDA) approval to conduct the first U.S human trial to investigate the safety and effectiveness of this method. They and their team will conduct this work at Nationwide Children’s Hospital.
“The fundamental problem faced by surgeons caring for children with congenital anomalies (defects that are present at birth) is the lack of sufficient tissue for reconstruction that is capable of growth,” said Mark Galantowicz, MD, FACS, Chief of Cardiothoracic Surgery and Co-Director of The Heart Center at Nationwide Children’s Hospital, as well Associate Professor of Surgery at The Ohio State University College of Medicine. “Tissue engineering is the process by which the child’s own cells are used to ‘grow’ new tissue or organs for repair of these birth defects and it holds the incredibly exciting potential to completely change how we care for our patients.”
Dr. Breuer and Dr. Shinoka will serve as Co-Directors of the new Tissue Engineering Program at Nationwide Children’s. Dr. Breuer will also serve as the Director for Tissue Engineering in The Ohio State University Wexner Medical Center’s new Center for Regenerative Medicine and Cell Based Therapies.
“The careers of Dr. Breuer and Dr. Shinoka exemplify what can be accomplished by highly focused surgeons with unwavering dedication to solving a problem faced by pediatric patients,” said R. Lawrence Moss, MD, Surgeon-in-Chief at Nationwide Children's Hospital and the E. Thomas Boles Jr., Professor of Surgery at The Ohio State University College of Medicine.
Following medical school at Dartmouth and training in Surgery and Pediatric Surgery at Brown University, Dr. Breuer served as the Chief of Pediatric Surgery for the United States Air Force. He then joined Yale University where he is currently Director of Tissue Engineering and Associate Professor of Surgery and of Pediatrics. At Yale, Dr. Breuer assembled a spectacular team and began to fulfill his longstanding dream of building blood vessels for children with heart defects. He obtained National Institutes of Health (NIH) funding upon first submission and currently holds three major NIH grants, a grant from the American Heart Association, and extensive industry funding. He has received numerous honors recognizing his contributions, including the Jacobsen Promising Investigator Award from the American College of Surgeons which is given to the most innovative young surgical investigator in the country.
Dr. Shinoka received his medical degree at Hiroshima University and his PhD in biomedical engineering at Tokyo Women’s Medical University. He was a leading clinical congenital heart surgeon at the Heart Institute of Japan before joining Yale University, where he has been Director of Pediatric Cardiovascular Surgery and Associate Professor of Surgery and of Pediatrics for the last five years. Dr. Shinoka is a successful surgeon-scientist, conducting nearly two decades of increasingly sophisticated tissue engineering research, both bench-top and translational. As an accomplished clinical congenital heart surgeon, Dr. Shinoka will join the Heart Center surgical team at Nationwide Children’s and will also be involved in the Heart Center’s Research initiatives that resonate well with his foundation in congenital heart disease translational research.
“We are delighted at the prospect of working with Dr. Breuer in our new Center for Regenerative Medicine and Cell Based Therapies,” said Steven Gabbe, MD, Senior Vice President for Health Sciences and CEO of the Wexner Medical Center at The Ohio State University. “The goal of our Center is to work with partners such as Nationwide Children’s and Battelle to discover novel treatments, and Dr. Breuer’s work is certainly indicative of the kind of research and clinical care we want to foster.”
May 18, 2012: Columbus Business First
Heal Thyself: Tissue on Demand
Nanofiber Solutions LLC in the TechColumbus incubator is set to start production in July of lab dishes and microscope slides laced with custom-made ultra-thin fibers that researchers say work better than formless gel for growing cells. The company has created artificial objects that can be implanted in the human body where cells can populate and grow blood vessels around the object in incorporate as part of the human body. The company is working with Ohio State's Center for Regenerative Medicine and Cell-Based Therapies to bring tissue-replacement surgery to Wexner Medical Center. Dr. Chandan Sen is quoted. More...
May 15, 2012: CoE 2012 "Building Bridges" Excellence Award to Prof. Chandan K Sen
The “Building Bridges” Excellence Award for the College of Engineering was established in 2007 and consists of $1,500 along with an award. The award is presented each year to a non-COE faculty member at Ohio State University whose collaborative work with the College of Engineering has advanced the excellence, impact and reputation of both colleges and the University. The award will be presented at annual College of Engineering Faculty Awards Banquet.
The award will be made to an individual faculty member outside of the College of Engineering for demonstrated excellence and accomplishment in the development and implementation of collaborative activities and programs between their academic unit and the College of Engineering. Consideration will be given to how this collaboration advances excellence and impact in education, research, and/or outreach and engagement of both organizations.
College of Engineering Faculty and staff may make nominations. Please limit your nomination to two pages or less and provide supporting materials that are brief and concise, yet with sufficient information to permit a rational selection. The nominating letter should address the following:
•Describe the primary activity and accomplishment that supports consideration for the “Building Bridges”
•Explain how this activity and accomplishment promotes the achievement of excellence and impact in the College of Engineering and other organizations within the University.
Nominations should also include a citation of no more than 50 words, highlighting the reasons for the nomination; this citation will be used in the program if the nominee is selected for this award.
The College Awards Committee will evaluate applicants and make a recommendation to the Dean of the College of Engineering, who will select one or more award recipients each year.
April 19, 2012: The Wall Street Journal, MarketWatch.com
April 16, 2012: Columbus Business First