Collagen-mediated Second Harmonic Generation for the Purpose of Drug Delivery and Biological Imaging

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Collagen-mediated second harmonic generation for the purpose of drug delivery and biological imaging
Professor Robert Langer
Department of Chemical Engineering, MIT
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Professor Daniel Kohane
Laboratory for Biomaterials and Drug Delivery, Boston Children's Hospital
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Aoune Barhoumi
Department of Anaesthesia, Boston Children's Hospital
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Tod Woolf
MIT Technology Licensing Officer
Patent Protection

Harmonic generation for activation of species and/or delivery of species to a target environment

US Patent 9,168,389
NIR-Triggered Drug Delivery by Collagen-Mediated Second Harmonic Generation
Advanced Healthcare Materials, Volume 4, Issue 8, pages 1159–1163, June 3, 2015


Drug delivery via collagen-mediated second harmonic generation (SHG) is of interest to both pharmaceutical and cosmetic companies seeking a system by which to develop or improve spatiotemporally controlled, photoreactive delivery of compounds to a variety of tissues. Additionally, collagen-mediated SHG can be utilized for the imaging of fine tissue structures at single-cell resolution. 

Problems Addressed

Photoreactive drug delivery systems often require high-energy ultraviolet (UV) light to activate a molecule or trigger its release. This presents a challenge due to the low tissue penetration and high phototoxicity of UV radiation. Second harmonic generation—the process by which two photons of equal energy combine to generate one photon of twice the energy—allows for the upconversion of safely penetrative, low-energy near-infrared (NIR) to high-energy UV, which can then induce activation of a photosensitive material. Whereas this process often entails the use of either sophisticated lasers or biologically incompatible elements, collagen is a nontoxic upconverting SHG material that, in combination with inexpensive continuous-wave lasers and photosensitive scaffolds, offers a relatively safe and cost-effective means of drug delivery.


This method comprises the use of collagen as a biocompatible SHG material in combination with photosensitive drug delivery elements to provide the light-inducible release or activation of a molecule at a target site. Collagen-mediated SHG converts NIR to UV, which is then used to physically or chemically alter a photosensitive material that, when disrupted, promotes the release or activation of a drug. Examples of such materials include (but are not limited to) photocleavable linkers, photosensitive micelles that encapsulate a drug, and encapsulated SHG nanocrystals such as LiNbO3 and BaTiO3 that assist in the photon upconversion process. As the drug of interest can be linked to either collagen or SHG nanocrystals, the target tissue need not contain collagen, thus expanding the scope of delivery regions. 


  • Low-energy NIR radiation allows for increased tissue penetration
  • Collagen is nontoxic and can be used to convert NIR to UV without the use of organic solvents or rare earth elements of questionable biocompatibility
  • Allows for the use of less expensive continuous-wave lasers as an excitation source, eliminating the need for highly sophisticated ultrashort pulse-emitting lasers