Various technologies exist in which parts of an animal or human body may be imaged so as to aid in diagnosis and therapy of medical disorders. One of techniques that is now widely used in diagnostic imaging various parts of the body is ultrasound. This technique involves the use of an ultrasound transducer to generate and receive sound waves. The transducer is placed on the body surface over an area to be imaged and sound waves generated by the transducer are directed to that area. The transducer then detects sound waves reflected from the underlying area and translates the data into images.
The basis for ultrasound imaging is that, when ultrasonic energy is transmitted through a substance, the acoustic properties of the substance will depend upon the velocity of the transmissions and the density of the substance. Changes in the substance's acoustic properties will be most prominent at the interface of different substances (i.e., solids, liquids and gases). As a consequence, when ultrasound energy is directed through various media, the changes in acoustic properties at such interfaces will change the reflection characteristics, resulting in a more intense sound reflection signal received by the ultrasound transducer.
Early ultrasound techniques suffered from a lack of clarity. As a result, extensive efforts were undertaken to improve the ultrasonic equipment. In addition, contrast agents were introduced into the bloodstream in an effort to obtain enhanced images. Many of these contrast agents were liquids containing microbubbles of gas. These contrast agents themselves are intense sound wave reflectors because of acoustic differences between the liquids and the gas microbubbles enclosed therein. Hence, when these contrast agents are injected into the bloodstream and perfuse the microvasculature of the tissue, clearer images of the tissue may be produced.
A number of different contrast agents are known in the art. For example, Feinstein discloses microbubbles formed from protein solutions, such as those formed from albumin, in U.S. Pat. No. 4,774,958. Microbubbles formed from gelatin are described as suitable contrast agents in U.S. Pat. No. 4,276,885. U.S. Pat. No. 4,684,479 discloses lipid-coated microbubbles which, because of their excellent in vitro stability, were suspected and recently confirmed to be very long-lived in vivo and, hence, are particularly well suited for diagnostic and therapeutic ultrasound applications. The method for preparing the microbubbles disclosed in the '479 patent is not, however, sufficient to allow for the large scale production of medical grade microbubbles.
One of the limitations of diagnostic ultrasound is that it is of very limited use preoperatively in neurosurgical applications because of the presence of bone, and in particular, the skull. Accordingly, magnetic resonance imaging ("MRI"), which is also quite sensitive to tissue pathology, has been rapidly accepted as a technique for neurological diagnosis. MRI of the brain is conducted preoperatively, to provide an image which the surgeon can then consult during an operation.
Initially, MRI was conducted without the aid of a contrast agent. However, the poor specificity of MRI in neurological diseases soon became evident. Contrast agents are now also available to enhance MRI imaging. The best known MRI contrast agents are paramagnetic metal ion chelates with low toxicity. These include manganese, iron and gadolinium metal ions which have been chelated with diethylenetriaminepentaacetic acid or ethylenediaminetetraacetic acid. See, for example, Carr et al, The Lancet, 1:484-486 (1984); Runge et al, Magnetic Resonance Imaging, 3:27-35 (1985); Lauffer et al, Magnetic Resonance Imaging, 3:11-16 (1985); and Lauffer et al, Magnetic Resonance Imaging, 3:541-548 (1986).
The foregoing techniques provide medical personnel with the ability to obtain accurate images under a broad range of conditions. There is, however, still a need for a contrast agent which could be-used for both ultrasonic imaging and MRI. For example, while MRI is the method of choice in neurological preoperative diagnosis, real time imaging with MRI during a surgical procedure is not possible. This is because of the massive size of the equipment required for MRI. Yet real time imaging during surgery is often desirable, particularly when the surgeon has reason to believe there has been a shift in position of tissue due to invasion by the surgical procedure and/or change in intracranial pressure. Although ultrasound imaging can be performed during surgery, the current unavailability of a contrast agent which can be used in both ultrasonic imaging and MRI renders anatomical correlation between the preoperative and operative images less reliable.
In addition to diagnostic applications, low frequency ultrasound has also been used therapeutically by physiotherapists to treat a variety conditions. Ultrasound is now also being investigated in the treatment of malignant tumors, through the effects of heat and cavitation. Quan et al, Phys. Med. Biol., 34:1719-1731 (1989) describe a five element ultrasound transducer array potentially useful in the treatment of malignant tumors through the effects of heat. When heat is used in tumor destruction, the tumors are heated to a temperature between 42.degree. and 45.degree. C., producing cellular damage. ter Haar et al, Phys. Med. Biol., 34:1743-1750 (1989), discuss the potential use of high intensity, focused ultrasound in the selective destruction of tumors, without damage to intervening tissues. Heretofore, no one has suggested a method of enhancing the effects of ultrasound through the use of gas-in-liquid microbubbles.
Accordingly, it is an object of the present invention to provide a process from the production of concentrated suspensions of medical grade, lipid-coated microbubbles.
Another object of the present invention is to provide paramagnetically-labeled lipid coated microbubbles suitable for use in ultrasonic imaging and MRI.
A still further object of the present invention is to provide a method for enhancing the selective destruction of tumors by ultrasound through the use of lipid-coated microbubbles.