Un sustituto de la sangre (también llamado sangre artificial o sustituto de la sangre ) es una sustancia que se utiliza para imitar y cumplir algunas funciones de la sangre biológica . Su objetivo es proporcionar una alternativa a la transfusión de sangre , que consiste en transferir sangre o productos derivados de la sangre de una persona a otra. Hasta ahora, no existen sustitutos de la sangre que transporten oxígeno bien aceptados , que es el objetivo típico de una transfusión de glóbulos rojos ; Sin embargo, existen expansores de volumen no sanguíneos ampliamente disponibles.para casos en los que solo se requiera restauración de volumen. Estos están ayudando a los médicos y cirujanos a evitar los riesgos de transmisión de enfermedades y supresión inmunológica, abordar la escasez crónica de donantes de sangre y abordar las preocupaciones de los testigos de Jehová y otras personas que tienen objeciones religiosas a recibir transfusiones de sangre.
Las principales categorías de sustitutos de la sangre "portadores de oxígeno" que se persiguen son los portadores de oxígeno basados en hemoglobina (HBOC) y los portadores de oxígeno basados en perfluorocarbono (PFBOC). [1] Las terapias de oxígeno se encuentran en ensayos clínicos en los EE. UU. Y Europa , y Hemopure está disponible en Sudáfrica .
Historia
Después de que William Harvey descubrió las vías sanguíneas en 1616, muchas personas intentaron usar líquidos como cerveza, orina, leche y sangre de animales no humanos como sustituto de la sangre. [2] Sir Christopher Wren sugirió el vino y el opio como sustitutos de la sangre. [3]
A principios del siglo XX, el desarrollo de la medicina transfusional moderna iniciado a través del trabajo de Landsteiner y sus coautores abrió la posibilidad de comprender el principio general de la serología de grupos sanguíneos. [4] Al mismo tiempo, se lograron avances significativos en los campos de la fisiología del corazón y la circulación, así como en la comprensión del mecanismo de transporte de oxígeno y oxigenación tisular. [5] [6]
Las restricciones en la medicina transfusional aplicada, especialmente en situaciones de desastre como la Segunda Guerra Mundial, sentaron las bases para una investigación acelerada en el campo de los sucedáneos de la sangre. [7] Los primeros intentos y el optimismo en el desarrollo de sustitutos de la sangre se enfrentaron muy rápidamente a efectos secundarios importantes, que no pudieron eliminarse rápidamente debido al nivel de conocimiento y tecnología disponibles en ese momento. La aparición del VIH en la década de 1980 renovó el ímpetu para el desarrollo de sustitutos de la sangre seguros para las infecciones. [3] La preocupación del público por la seguridad del suministro de sangre aumentó aún más por la enfermedad de las vacas locas . [3] [8] La disminución continua de la donación de sangre combinada con el aumento de la demanda de transfusión de sangre (aumento del envejecimiento de la población, aumento de la incidencia de diagnósticos invasivos, quimioterapia e intervenciones quirúrgicas extensivas, ataques terroristas, conflictos militares internacionales) y estimación positiva de los inversores en la rama de biotecnología creó un entorno positivo para un mayor desarrollo de sustitutos de la sangre. [8]
Efforts to develop blood substitutes have been driven by a desire to replace blood transfusion in emergency situations, in places where infectious disease is endemic and the risk of contaminated blood products is high, where refrigeration to preserve blood may be lacking, and where it might not be possible or convenient to find blood type matches.[9]
Enfoques
Efforts have focused on molecules that can carry oxygen, and most work has focused on recombinant hemoglobin, which normally carries oxygen, and perfluorocarbons (PFC), chemical compounds which can carry and release oxygen.[9][10]
The first approved oxygen-carrying blood substitute was a perfluorocarbon-based product called Fluosol-DA-20, manufactured by Green Cross of Japan. It was approved by the Food and Drug Administration (FDA) in 1989. Because of limited success, complexity of use and side effects, it was withdrawn in 1994. However, Fluosol-DA remains the only oxygen therapeutic ever fully approved by the FDA. As of 2017 no hemoglobin-based product had been approved.[9]
Perfluorocarbon based
Perfluorochemicals are not water soluble, so will not mix with blood, therefore emulsions must be made by dispersing small drops of PFC in water. This liquid is then mixed with antibiotics, vitamins, nutrients and salts, producing a mixture that contains about 80 different components, and performs many of the vital functions of natural blood. PFC particles are about 1/40 the size of the diameter of a red blood cell (RBC). This small size can enable PFC particles to traverse capillaries through which no RBCs are flowing. In theory this can benefit damaged, blood-starved tissue, which conventional red cells cannot reach. PFC solutions can carry oxygen so well that mammals, including humans, can survive breathing liquid PFC solution, called liquid breathing.
Perfluorocarbon-based blood substitutes are completely man-made; this provides advantages over blood substitutes that rely on modified hemoglobin, such as unlimited manufacturing capabilities, ability to be heat-sterilized, and PFCs' efficient oxygen delivery and carbon dioxide removal. PFCs in solution act as an intravascular oxygen carrier to temporarily augment oxygen delivery to tissues. PFCs are removed from the bloodstream within 48 hours by the body's normal clearance procedure for particles in the blood – exhalation. PFC particles in solution can carry several times more oxygen per cubic centimeter (cc) than blood, while being 40 to 50 times smaller than hemoglobin.
Fluosol was made mostly of perfluorodecalin or perfluorotributylamine suspended in an albumin emulsion. It was developed in Japan and first tested in the United States in November 1979.[11] In order to "load" sufficient amounts of oxygen into it, people who had been given it had to breathe pure oxygen by mask or in a hyperbaric chamber.[12] It was approved by the FDA in 1989,[13] and was approved in eight other countries.[citation needed] Its use was associated with a reduction in ischemic complications and with an increase in pulmonary edema and congestive heart failure.[14] Due to difficulty with the emulsion storage of Fluosol use (frozen storage and rewarming), its popularity declined and its production ended in 1994.[9]
Name | Sponsor | Description |
---|---|---|
Oxycyte | Oxygen Biotherapeutics | Tested in a Phase II-b Trials in the United States. Targeted as an oxygen therapeutic rather than a blood substitute, with successful small-scale open label human trials treating traumatic brain injury at Virginia Commonwealth University.[15] The trial was later terminated.[16] |
PHER-O 2 | Sanguine Corp | In research |
Perftoran | Russia | Contains perfluorodecalin and perfluoro-N-(4-methylcyclohexyl)-piperidine along with a surfactant, Proxanol-268. It was developed in Russia and as of 2005 was marketed there.[17] |
NVX-108 | NuvOx Pharma | In a Phase Ib/II clinical trial where it raises tumor oxygen levels prior to radiation therapy in order to radiosensitize them.[18] |
Oxygent was a second-generation, lecithin-stabilized emulsion of a PFC that was under development by Alliance Pharmaceuticals.[19][20][21] In 2002 a Phase III study was halted early due an increase in incidences of strokes in the study arm.[22]
Haemoglobin based
Haemoglobin is the main component of red blood cells, comprising about 33% of the cell mass. Haemoglobin-based products are called haemoglobin-based oxygen carriers (HBOCs).
Unmodified cell-free haemoglobin is not useful as a blood substitute because its oxygen affinity is too high for effective tissue oxygenation, the half-life within the intravascular space that is too short to be clinically useful, it has a tendency to undergo dissociation in dimers with resultant kidney damage and toxicity, and because free haemoglobin tends to take up nitric oxide, causing vasoconstriction.[3][23][24][25]
Efforts to overcome this toxicity have included making genetically engineered versions, cross-linking, polymerization, and encapsulation.[9]
HemAssist, a diaspirin cross-linked haemoglobin (DCLHb) was developed by Baxter Healthcare; it was the most widely studied of the haemoglobin-based blood substitutes, used in more than a dozen animal and clinical studies.[7] It reached Phase III clinical trials, in which failed due to increased mortality in the trial arm, mostly due to severe vasoconstriction complications.[9][7] The results were published in 1999.[26]
Hemolink (Hemosol, Inc., Mississauga, Canada) was a haemoglobin solution that contained cross-linked an o-rafinose polymerised human haemoglobin,[9] which struggled after Phase II trials were halted in 2003 on safety concerns.[27] It declared bankruptcy in 2005.[28]
Hemopure was developed by Biopure Corp and was a chemically stabilized, cross-linked bovine (cow) haemoglobin in a salt solution intended for human use; the company developed the same product under the trade name Oxyglobin for veterinary use in dogs. Oxyglobin was approved in the US and Europe and was introduced to veterinary clinics and hospitals in March 1998. Hemopure was approved in South Africa and Russia. Biopure filed for bankruptcy protection in 2009.[29] Its assets were subsequently purchased by HbO2 Therapeutics in 2014.[citation needed]
PolyHeme was developed over 20 years by Northfield Laboratories and began as a military project following the Vietnam War. It is human haemoglobin, extracted from red blood cells, then polymerized, then incorporated into an electrolyte solution. In April 2009, the FDA rejected Northfield's Biologic License Application[30] and in June 2009, Northfield filed for bankruptcy.[31]
Dextran-Haemoglobin was developed by Dextro-Sang Corp as a veterinary product, and was a conjugate of the polymer dextran with human haemoglobin.
Hemotech was developed by HemoBiotech and was a chemically modified haemoglobin.
Somatogen developed a genetically engineered and crosslinked tetramer it called Optro. It failed in a phase II trial that was published in 2014 and development was halted.[9]
A pyridoxylated Hb conjugated with polyoxyethylene was created by scientists at Ajinomoto and eventually developed by Apex Biosciences, a subsidiary of Curacyte AG; it was called "PHP" and failed in a Phase III trial published in 2014, due to increased mortality in the control arm,[9][32] which led to Curacyte shutting down.[33]
Similarly, Hemospan was developed by Sangart, and was a pegylated haemoglobin provided in a powdered form. While early trials were promising Sangart ran out of funding and closed down.[9]
Stem cells
Stem cells offer a possible means of producing transfusable blood. A study performed by Giarratana et al.[34] describes a large-scale ex-vivo production of mature human blood cells using hematopoietic stem cells. The cultured cells possessed the same haemoglobin content and morphology as native red blood cells. The authors contend that the cells had a near-normal lifespan, when compared to natural red blood cells.
Scientists from the experimental arm of the United States Department of Defense began creating artificial blood for use in remote areas and transfuse blood to wounded soldiers more quickly in 2010.[35] The blood is made from the hematopoietic stem cells removed from the umbilical cord between human mother and newborn using a method called blood pharming. Pharming has been used in the past on animals and plants to create medical substances in large quantities. Each cord can produce approximately 20 units of blood. The blood is being produced for the Defense Advanced Research Projects Agency by Arteriocyte. The Food and Drug Administration has examined and approved the safety of this blood from previously submitted O-negative blood. Using this particular artificial blood will reduce the costs per unit of blood from $5,000 to equal or less than $1,000.[35] This blood will also serve as a blood donor to all common blood types. Pharmed blood may be used in human trials in 2013.[36]
Ver también
- Artificial Cells, Blood Substitutes, and Biotechnology
- Blood plasma substitute (disambiguation)
- Blood transfusion
- Bloodless surgery
- Erythromer
- Induced blood stem cells
- Theatrical blood
Referencias
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enlaces externos
- How Artificial Blood Works at HowStuffWorks