What are the next-generation blood substitutes?

Updated: Dec 11, 2018
  • Author: Sara J Grethlein, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Polyethylene glycol (PEG) hemoglobin (Enzon Pharmaceuticals, Bridgewater, NJ) was a conjugated bovine hemoglobin that was evaluated for use in cancer therapy to increase tumor oxygenation and enhance the efficacy of radiation and chemotherapy. [12, 13] However, at present, production of this product has been discontinued.

Hemospan (Sangart Inc., San Diego, Calif), also known as MP4OX, is a PEG-conjugated human hemoglobin currently undergoing clinical trials in the US and Europe. [14] In animal models Hemospan (MP4OX) has been shown to be effective in cases of hemorrhagic shock. [15] Adverse effects associated with the vasoactive properties of first-generation blood substitutes are not seen with Hemospan (MP4OX). At relatively low concentrations, Hemospan (MP4OX) is capable of transporting large amounts of oxygen. Sangart Inc. announced positive results from a phase II study for this product in November 2005.

The trial, conducted in Sweden, involved 90 patients undergoing hip arthroplasty. Patients were randomized to receive either Hemospan (MP4OX) or Ringer acetate (control) before induction of spinal anesthesia. Hemospan (MP4OX) was found to be well tolerated in the study group with no serious adverse effects attributed to the product during the trial period. The percentage of hypotensive episodes in the Hemospan (MP4OX) group was about 45% compared to 87% among controls. Incidence of intra-operative vasopressor use was about 15% in the Hemospan (MP4OX) group compared to 32% among controls. See Sangart Inc: Clinical Trials for more information on recent studies.

Pyridoxylated hemoglobin polyoxyethylene conjugate (PHP) is a conjugated hemoglobin developed by Apex Bioscience that completed a phase III trial in August 2009 in patients with shock associated with systemic inflammatory response syndrome. The study has been designed to evaluate the safety and efficacy of continuous IV infusion of PHP plus conventional vasopressor treatment versus continuous IV infusion of Plasma-lyte A plus conventional vasopressors as a treatment for restoring hemodynamic stability in SIRS patients with shock. See ClinicalTrials.gov, Identifier: NCT00021502, for more information.

For hemoglobin-based oxygen carriers cross-linked with enzymes, there has been an effort to synthesize compounds that not only perform the function of carrying oxygen, as do the molecules mentioned previously, but also harbor some of the enzyme activity that normal red blood cells possess. Polymerized hemoglobin has been cross-linked with catalase and superoxide dismutase to form a compound that, in animal models can not only carry oxygen but also remove oxygen radicals that are responsible for ischemia reperfusion injuries. [16]

Polyhemoglobin has also been cross-linked with tyrosinase to form a soluble complex that can carry oxygen and decrease the systemic levels of tyrosine. This agent can help increase the efficacy of chemotherapy and radiation therapy in tumor tissue and in a melanoma model has been shown to delay tumor growth without having significant adverse effects. [16]

Efforts have been made to encapsulate hemoglobin within a lipid-membrane to create a compound capable of carrying oxygen while not being associated with significant vasoconstriction. These liposomes appear to be retained in plasma for a significant period. However, they are difficult to produce and can activate the reticuloendothelial system, the complement pathway, and platelets. At present, the only institutions working actively on this product are in Japan.

The ultimate RBC substitute would contain not only hemoglobin but also other contents of the red blood cell also encapsulated in an artificial membrane. However, production of such a product would be extremely challenging. Efforts have been made to use polyactide, a biodegradable polymer that is converted to lactic acid in the body, to create artificial red blood cells. These cells contain hemoglobin along with the RBC enzyme complement including superoxide dismutase, methemoglobin reductase, and catalase. [16]

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