Manstein Lab
Call: 617-233-5054
Email: kaburke@mgh.harvard.edu
6172335054
kaburke@mgh.harvard.edu
Overview
The focus of the Manstein Lab is to conduct basic and clinical research related to the novel, energy-based devices, and procedures in dermatology for various medical and aesthetic dermatological conditions. Prior inventions include Fractional Photothermolysis, a revolutionary dermatological laser procedure, Selective Cryolipolysis, a novel concept of non-invasive fat removal, as well as Fractional Radiofrequency Needle Array, a technique to deliver radiofrequency energy to the dermis and below in a fractional thermal damage pattern.
Fractional Photothermolysis
Prior to the early 2000’s, laser skin resurfacing was a clinically effective treatment that involved using a pulsed CO2 laser or an Er:YAG laser to completely remove the epidermis. However, this treatment often resulted in severe side effects including immediate reactions like pain, oozing, crusting, and burning, as well as more long-term effects like scarring and pigmentary changes. Additionally, by damaging the entire epidermal layer, the keratinocyte response to wound healing was eliminated. In a significant paradigm shift, Dieter Manstein, in collaboration with Rox Anderson at MGH’s Wellman Center for Photomedicine, began exploring a new resurfacing procedure. Using lasers to cause ablation and/or thermal damage of multiple microscopic areas in the epidermis and dermis, separated by non-damaged areas of the skin, allows for rapid healing. The side effects prominent with full
resurfacing laser treatments are reduced as the epidermis is not fully removed, but the efficacy of the procedure is maintained with minimal damage to the epidermis. Because the damage to the skin is created through small and separated areas, nearby fibroblasts can lay down new collagen and shorter migratory pathways for keratinocytes are established for faster epidermal repair. The result is an efficient and successful treatment of photoaged skin. This new technology became known as the ‘fractional laser’ and is now common in dermatology offices around the world. Research in the Manstein Lab continues to expand the use of fractional lasers to new aesthetic and medical indications.
Selective Cryolipolysis
Based on a serendipitous observation of an infant’s cheek after sucking on a popsicle, Dieter Manstein and Rox Anderson at MGH’s Wellman Center for Photomedicine, collaborated to study the effect of selectively cooling adipose tissue to achieve fat reduction. Research began in 2000 to study the effects of cooling on adipocytes while sparing skin, nerves, vessels, and muscles. The technology was developed at MGH and commercialized through the formation of the startup, Juniper Medical, in 2005. Juniper Medical became Zeltiq Aesthetics, the company that achieved FDA approval in September 2010 andsuccessfully launched cryolipolysis technology through the CoolSculpting product line. Cryolipolysis is considered a safe method of fat removal treatment and is often utilized instead of liposuction for its non-invasive procedure and lack of recovery time. Now owned by Allergan, CoolSculpting treatments are available in over 50 countries. Meanwhile, research into the effects of cooling on various tissues including adipose tissue continues in the Manstein Lab.
Fractional Radiofrequency Needle Array
Traditionally, aesthetic treatments using radiofrequency energy for skin rejuvenation applied energy at the surface of the skin resulting in epidermal damage and some depth of dermal damage. Building on the fractional principles developed with his laser research, Dieter Manstein considered how to deliver a fractional pattern of dermal damage deeper in the skin while sparing the epidermis. An array of needles to deliver radiofrequency energy to deeper tissues offered the solution. Early research showed proof-of-concept that resulted in a patent license to a local Boston-based medical device company, Candela, to commercialize the technology. Candela currently makes and sells the Profound Radiofrequency Needling device for treating various aesthetic dermatology indications
Research Projects
Imaging
Optical Coherence Tomography
Like ultrasound imaging, optical coherence tomography (OCT) enables non-invasive, in situ cross-sectional visualization of biological tissue. Instead of sound, OCT uses low-coherence light to achieve micrometer-scale resolution, making it highly suitable for dermatologic applications. Conventional OCTA captures only a momentary snapshot of capillary perfusion, without resolving true microvascular architecture. As a result, repeated imaging of the same site is often variable and does not reliably reflect the full capacity of the capillary bed. To address this, the Manstein Lab developed reactive hyperemia OCT (RH-OCT) to capture maximal perfusion of the cutaneous capillary bed, and is applying it in clinical studies to evaluate microvascular function across conditions such as smoking, diabetes, and post-laser treatment.
To complement this, the Manstein Lab is advancing dynamic contrast microscopic OCT (dmOCT), which analyzes temporal signal fluctuations to quantify intrinsic tissue dynamics. This approach enables label-free functional imaging by capturing motion-related contrast linked to cellular and metabolic activity. Recent work by Felix Hilge et al., demonstrate that dmOCT can sensitively detect early ultraviolet (UV)-induced skin damage by identifying dynamic changes in the epidermis and dermis prior to visible or histologic alterations.
Together, these technologies provide a comprehensive, non-invasive imaging platform for assessing both vascular physiology and tissue metabolism, enabling longitudinal monitoring of skin health without the need for biopsy.
Relevant Publications:
Wang-Evers, M., Casper, M.J., Glahn, J. et al. Assessing the impact of aging and blood pressure on dermal microvasculature by reactive hyperemia optical coherence tomography angiography. Sci Rep 11, 13411 (2021). doi: 10.1038/s41598-021-92712-z
F. Hilge, M. Wang-Evers, L. Buhl, H. Downs, M. Dolling, L. Pohl, R. Birngruber, H. Schulz-Hildebrandt, G. Hüttmann, and D. Manstein, "Label-free visualization and quantitative analysis of Far UV-C skin safety with dynamic optical coherence tomography with subcellular resolution," Biomed. Opt. Express 16, 3682-3701 (2025).
Pre-Clinical Research
In mice, the adipose tissue layer is thin enough to image using OCT. The Manstein Lab has a significant mouse research effort examining the effects of cooling and/or cryolipolysis on fat in mice. We are examining the mechanisms of adipose tissue loss, the browning of adipose tissue as a result of localized cooling, and effects on metabolic activity after cryolipolysis.
Relevant Publications:
Kepp, T., Droigk, C., Casper, M., Evers, M., Hüttman, G., Salma, N., Manstein, D., Heinrich, M.P., Handels, H. Segmentation of mouse skin layers in optical coherence tomography image data using deep convolutional neural networks. Biomedical Optics Express. 2019 Jun 21;10(7):3484-3496. doi: 10.1364/BOE.10.003484. eCollection 2019 Jul 1.
Casper, M., Schulz-Hildebrandt, H., Evers, M., Birngruber, R., Manstein, D., Hüttman, G. Optimization-based vessel segmentation pipeline for robust quantification of capillary networks in skin with optical coherence tomography angiography. Journal of Biomedical Optics. 2019 Apr;2494):1-11. doi: 10.1117/1.JBO.24.4.046005.
Fluorescence Lifetime Imaging Microscopy (FLIM)
FLIM is a well-established imaging method that analyzes the lifetime of a fluorophore rather than its intensity. The Manstein Lab is focused on using this technique for evaluating adipose tissue metabolism. There are three types of fat cells that have metabolic functions in the body; white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue (BeAT). We are looking at BAT and BeAT as targets for treating obesity due to their ability to dissipate energy as heat via nonshivering thermogenesis. By stimulating and activating BAT and BeAT, lipolysis and metabolic activity is increased, resulting in higher whole-body energy expenditure and a reduction in fat. However, traditional metabolic analysis faces many difficulties evaluating the activation of brown fat in a heterogeneous environment and monitoring metabolic activity over time. Two-photon FLIM is used to identify the naturally occurring auto-fluorescent molecule nicotinamide adenine dinucleotide (NADH) for label-free quantification of metabolic activity. Compared to traditional FLIM analysis that utilizes a two-lifetime model of NADH, the Manstein Lab expanded to a four-lifetime model of NADH resulting in superior metabolic assessment. The four-lifetime components can be mapped to specific cellular compartments to create a novel optical biomarker named the mitochondrial-cytoplasmic-ratio (MCR) that accurately reflects the shifts in mitochondrial and cytoplasmic NADH distribution and binding states. Additionally, the new MCR metric correlates very well with the oxygen consumption rate as measured by traditional methods such as an extracellular flux analyzer. This widely applicable approach constitutes a powerful tool for monitoring cellular metabolism, and we are currently using it for wound healing and stem cell differentiation studies.
Relevant Publications:
Evers, M., Salma, N., Osseiran, S., Casper, M., Birngruber, R., Evans, C.L., Manstein, D. Enhanced quantification of metabolic activity for individual adipocytes by label-free FLIM. Scientific Reports. 2018 Jun 8;8(1):8757. doi: 10.1038/s41598-018-27093-x.
Fractional Technology
Fractional laser technology was co-invented by Dieter Manstein, and it utilizes non-ablative or ablative laser treatments to create microscopic treatment zones (MTZs) in skin. Laser exposures thermally damages the target skin within small areas of diameters, generally less than 0.5 mm. Tissue surrounding the MTZs remains unexposed to the laser and thermal damage, increasing the speed and efficacy of wound healing in the MTZs. Fractional laser technology is commonly used for the treatment of photodamaged skin, pigmentation disorders, actinic keratosis, rhytides, and wrinkles. It is also vital in restoring scarred skin caused by acne, surgery, and burns. CO2 lasers are commonly used during fractional ablation as the tissue is immediately evaporated without causing significant thermal damage. However, there is a need to optimize the settings of the CO2 laser, such as wavelength, energy per pulse, pulse duration, pulse number, and temporal pulse shape, without causing significant thermal damage for improved treatment of dermatological conditions. Current research in the Manstein Lab is focused on developing new laser systems that improve upon the feasibility of the CO2 laser for improved dermal ablation and maximum skin tightening.
Alternative lasers like CO lasers and Thulium fiber lasers have the potential to enhance treatment of dermatological conditions. Though less renowned than CO2 lasers, literature has suggested that adaptations to CO lasers would allow smaller spot sizes than those feasible in CO2 lasers. Additionally, Thulium fiber lasers, which are currently used in non-ablative treatments of melasma and mild to moderate photodamage, might also be useful for ablative treatments. Current research focuses on the effect of these lasers on skin specimens to evaluate differences in etch depth, thermal damage, and ablation-to-coagulation ratio (ACR). Laser characteristics such as wavelength, beam diameter, radiant exposure, pulse duration, and temporal pulse shape are altered to establish corresponding changes in etch depth, thermal damage, and ACR on the skin. Further fractional technology research focuses on enhancing skin rejuvenation without causing adverse side effects, as well as adapting laser parameters to create smaller ablation diameters in the skin for increased wound healing.
Relevant Publications:
Laubach, H.J., Tannous, Z., Anderson, R.R., Manstein, D. Skin responses to fractional photothermolysis. Lasers in Surgery and Medicine. 2006 Feb;38(2):142-9. doi: 10.1002/lsm.20254.
Manstein, D., Herron, G.S., Sink, R.K., Tanner, H., Anderson, R.R. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers in Surgery and Medicine. 2004;34(5):426-38. doi: 10.1002/lsm.20048.
Cooling
Together with Rox Anderson at MGH’s Wellman Center for Photomedicine, Dieter Manstein co-invented the successful cryolipolysis technology called CoolSculpting which has been widely used since 2010. CoolSculpting is a non-invasive and safe treatment for fat removal as it selectively freezes adipocytes while leaving blood vessels, muscles, and nerves intact. Approximately 20-25% decrease in fat tissue volume occurs in treated areas within one to three months post treatment.
Through pre-clinical and human clinical studies, the Manstein Lab is furthering research into tissue cooling by exploring the mechanisms of adipose tissue loss after cryolipolysis, studying how adipose tissue cooling might induce browning of fat tissue to generate increased energy consumption, and developing devices using cooling to effect pain management during various aesthetic dermatology procedures.
Relevant Publications:
Zelickson, B., Egbert, B.M., Preciado, J., Allison, J., Springer, K., Rhoades, R.W., Manstein, D. Cryolipolysis for noninvasive fat cell destruction: initial results from a pig model. Dermatological Surgery: official publication for American Society for Dermatological Surgery [et al.]. 2009 Oct;35(10):1462-70. doi: 10.1111/j.1524-4725.2009.01259.x. Epub 2009 Jul 13.Z
Manstein, D., Laubach, H., Watanabe, K., Farinelli, W., Zurakowski, D., Anderson, R.R. Selective cryolysis: a novel method of non-invasive fat removal. Lasers in Surgery and Medicine. 2008 Nov;40(9):595-604. doi: 10.1002/lsm.20719.
Immuno-Oncology
Laser-mediated immuno-oncology
It is well known that ablative fractional photothermolysis (aFP) produces unique wound-healing responses in tissue. Ablative fractional thermal injury in skin tissue, for instance, recruits the immune system to remove thermally damaged tissue without causing scarring. We are exploring how aFP of solid tumors might generate a response in the immune system (innate and adaptive immunity), in conjunction with various immune stimulating agents, to better attack both the tumor that was treated with laser as well as other non-treated remote tumors in the body.
Relevant Publications:
Kawakubo, M., Cunningham, T.J., Demehri, S., Manstein, D. Fractional Laser Releases Tumor-Associated Antigens in Poorly Immunogenic Tumor and Induces Systemic Immunity. Scientific reports. 2017 Oct 6;7(1):12751. Doi: 10.1038/s41598-017-13095-8.
Kawakubo, M., Demehri, S., Manstein, D. Fractional laser exposure induces neutrophil infiltration (N1 phenotype) into the tumor and stimulates systemic anti-tumor immune response. PLoS One. 2017 Sep 18;12(9):e0184852. Doi: 10.1371/journal.pone.0184852. eCollection 2017.
Laser-Assisted Drug Delivery
A major area of contribution is the development of laser-assisted drug delivery (LADD) and transdermal transport mechanisms. Recent studies using OCT-guided analysis have shown that ablative fractional lasers can create microchannels that significantly enhance penetration of topically applied agents such as poly-L-lactic acid, with uptake rates exceeding 80% in certain channel geometries. These findings highlight the importance of laser–tissue interaction parameters such as channel depth and morphology in determining therapeutic delivery efficiency, positioning fractional lasers as powerful tools for controlled intradermal drug deposition.
Relevant Publications:
T. Suwan P, Ahn GR, Sumner R, Paithankar D, Yaroslavsky IV, Altshuler G, et al. Novel 40 µm spot size 3050/3200 nm DFG laser versus CO2 laser for laser-assisted drug delivery. Lasers Surg Med. 2024;56:186–196. https://doi.org/10.1002/lsm.23755
Energy-Based Modulation of Skin Physiology
More broadly, our research explores how energy-based devices can modulate skin physiology beyond structural remodeling. Recent investigations examine how controlled thermal or mechanical injury influences inflammation, vascular responses, and systemic signaling pathways. This includes work on how localized treatments may induce distal biological effects, highlighting the skin’s role as an active interface in systemic physiology. These studies highlight new opportunities for dermatologic interventions to extend beyond local effects, enabling broader therapeutic modulation of systemic physiology.
Relevant Publications:
Salma, N. and Wang-Evers, M. et al. Large area fractional laser treatment of mouse skin increases energy expenditure. iScience 27 (2024). https://doi.org/10.1016/j.isci.2023.108677
Michael Wang-Evers, Ph.D.
Associate Director of R&D, Assistant Professor, Dermatology
Jenifer Perry, BA Finance, BA Management, MBA Corporate Renewal and Marketing
Financial Analyst
Kellie A. Burke
Administrative Assistant
Heather Downs, BS
Manstein Lab Manager
Garam Ahn, M.D., Ph.D.
Instructor, Dermatology, Senior Scientist
Sarfaraz Quadri, MS
Senior Research Technologist
Felix Hilge, MS
Senior Research Technologist
James Sefton, M.S.
Senior Research Technologist
Alice Viotti
Research Fellow
Marielos Posada
Research Fellow
Peter Berenstein
Research Fellow
Inbal Rahamin, Ph.D.
Consultant
Elisabeth Roider, M.D.
Consultant
Alicia Van Cott, NP
NP for Research Studies at CURTIS for Manstein Lab
Amelia Carlson, B.S.
CRC II for Research Studies at CURTIS for Manstein Lab
Mitchell Jones, BS
Lab Technician
Reginald Birngruber, M.D.
Consultant