Platform Technology for Treating Disorders Involving the Inflammatory Process

"Unexpected but compelling results"

A normal inflammatory response promotes healing but inflammation that is out of control is dangerous. For patients in acute renal failure it can precipitate sepsis or SIRS and lead to multi-organ failure and death.

The original bioartificial kidney configuration was observed to have a beneficial effect on uncontrolled inflammatory response induced by acute renal failure.

The living cells within the device were seen to play a key role in regulating the body's inflammatory response.

Additionally, and completely unexpectedly, the device was seen to be effective in modulating inflammation even without the living cells.

We conceived and developed new configurations of the device to take advantage of the new findings.The new configurations are predicated on the ability of the device to sequester and deactivate cells that are key to the inflammatory response. The device is called a Selective Cytophoresis Device, or "SCD". It is, essentially, a membrane device without living cells.

Activated neutrophils in a blood vessel within the kidney.
Inflammation is essential to the healing process when regulated, a critical threat when out of control.



Cytokines- for and against inflammation

Small messenger molecules called "cytokines" are essential in regulating the sequence of events that make up the inflammatory process. Anti-inflammatory cytokines suppress the reaction and pro-inflammatory cytokines promote it. Normally, the two are in balance (left).

In this illustration a small cut in the skin (center) triggers production of pro-inflammatory cytokines, prompting capillaries to become "leaky" and allowing outmigration of neutrophils to the wound site.

When healing is complete (right), pro- and anti-inflammatory cytokines return to balance.





Neutrophils in Inflammation

1. A specialized white blood cell (a neutrophil) and red blood cells are shown circulating in a typical blood vessel. 2. Chemical signals given off by invading bacteria prompt circulating neutrophils to turn on, or "prime". 3. Under continuing exposure to a toxic bacterial signal the primed neutrophil activates.
4. The activated neutrophill migrates out of the blood vessel into surrounding tissue. 5. The activated neutrophill destroys the threatening invader by engulfing it. 6. Its job done, the neutrophil dies off-- a kind of programmed suicide.
7. The dead neutrophill is itself removed-- by a scavenging macrophage, a cell that specializes in "clean-up". In disorders of inflammation an overabundance of neutrophils are produced and remain activated without turning off. The flood of activated neutrophils can damage healthy tissue.

A strategy of "catch and release"

zooming in for close-up of SCID
Zooming in on the SCD. Blood begins to flow through the SCD.
Inside the cartridge red cells and neutrophils flow around and between the fibers. Activated neutrophils are captured on the fibers' surfaces, deactivated, and released back into circulation.


New SCD-based therapies in development
Unwanted inflammation can be a factor in several serious medical conditions. We are researching ways to incorporate our basic SCID technology into therapeutic configurations for treating several disorders:

End Stage Renal Disease (ESRD)
A version for treating the hyperinflammation of ESRD is also in clinical trial. This is to be used in series with dialysis and is intended to control the chronic hyperinflammation that ESRD patients experience.

References for the Selective Cytopheretic Device:

    • Tumlin JA, Chawla L, Tolwani AJ, Mehta R, Dillon J, Finkel K, DaSilva JR, Astor BC, Yevzlin AS, Humes HD: The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multi-center pilot study. Seminars in Dialysis 2012; 25(6) DOI: 10.1111/sdi.12032.
    • Ding F, Yevzlin AS, Humes HD. A selective cytopheretic inhibitory device (SCD) accelerates renal recovery and improves mortality in ICU patients with AKI and MOF in an exploratory clinical study. ASAIO J2010; 56:140. PMID:21317636
    • Humes HD, Sobota JT, Ding F, Song JH, and the RAD Investigator Group.  A selective cytopheretic inhibitory device (SCD) to treat the immunologic dysregulation of acute and chronic renal failure.  Blood Purif 2010; 29:183-190. PMID: 20093825
    • Ding, F, Song, JH, Jung, JY, Lou, L, Wang, M, Charles, L, Westover, A, Smith, PL, Pino, CJ, Buffington, DA, Humes, HD. A Biomimetic Membrane Device that Modulates the Excessive Inflammatory Response to Sepsis. PLoS One 6:e18584, 2011. PMCID: PMC 3077371
    • Pino CJ, Lou L, Smith PL, Ding F, Pagani FD, Buffington DA, Humes HD.  A Selective Cytopheretic Inhibitory Device for Use During Cardiopulmonary Bypass Surgery . Perfusion 27:311-319, 2012. PMID:22508804
    • Pino CJ, Yevzlin AS, Lee K, Westover AJ, Smith PL, Buffington DA, Humes HD. Cell-Based Approaches for the Treatment of Systemic Inflammation. Nephrology Dialysis Transplantation, 2012; doi: 10.1093/ndt/gfs503
    • Ding F, Yevzlin AS, Xu ZY, Zhou Y, Xie QH, Liu JF, Zheng Y, DaSilva JR, Humes HD. The effects of a novel therapeutic device on acute kidney injury outcomes in the intensive care unit: a pilot study. ASAIO J. 2011;57(5):426-432. PMID: 21317636.
    • Pino CJ, Yevzlin AS, Tumlin J, Humes HD. Cell-Based Strategies for the Treatment of Kidney Dysfunction: A Review. Blood Purification, 2012;34:117-23. PMID: 23095410 DOI: 10.1159/000341649.
    • Pino CJ, Farokhrani A, Lou L, Smith PL, Johnston K, Buffington DA, Humes HD. Selective cytopheretic inhibitory device with regional citrate anticoagulation and portable sorbent dialysis. Artif Organs. 2013;37(2):203-210. PMID: 23067378