skip to main content

This content will become publicly available on May 16, 2025

Title: Engineering Low Volume Resuscitants for the Prehospital Care of Severe Hemorrhagic Shock

Globally, traumatic injury is a leading cause of suffering and death. The ability to curtail damage and ensure survival after major injury requires a time‐sensitive response balancing organ perfusion, blood loss, and portability, underscoring the need for novel therapies for the prehospital environment. Currently, there are few options available for damage control resuscitation (DCR) of trauma victims. We hypothesize that synthetic polymers, which are tunable, portable, and stable under austere conditions, can be developed as effective injectable therapies for trauma medicine. In this work, we design injectable polymers for use as low volume resuscitants (LVRs). Using RAFT polymerization, we evaluate the effect of polymer size, architecture, and chemical composition upon both blood coagulation and resuscitation in a rat hemorrhagic shock model. Our therapy is evaluated against a clinically used colloid resuscitant, Hextend. We demonstrate that a radiant star poly(glycerol monomethacrylate) polymer did not interfere with coagulation while successfully correcting metabolic deficit and resuscitating animals from hemorrhagic shock to the desired mean arterial pressure range for DCR – correcting a 60% total blood volume (TBV) loss when given at only 10% TBV. This highly portable and non‐coagulopathic resuscitant has profound potential for application in trauma medicine.

more » « less
Award ID(s):
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
Date Published:
Journal Name:
Angewandte Chemie International Edition
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    The maintenance of hemostasis to ensure vascular integrity is dependent upon the rapid conversion of zymogen species of the coagulation cascade to their enzymatically active forms. This process culminates in the generation of the serine protease thrombin and polymerization of fibrin to prevent vascular leak at sites of endothelial cell injury or loss of cellular junctions. Thrombin generation can be initiated by the extrinsic pathway of coagulation through exposure of blood to tissue factor at sites of vascular damage, or alternatively by the coagulation factor (F) XII activated by foreign surfaces with negative charges, such as glass, through the contact activation pathway. Here, we used transient particle tracking microrheology to investigate the mechanical properties of fibrin in response to thrombin generation downstream of both coagulation pathways. We found that the structural heterogeneity of fibrin formation was dependent on the reaction kinetics of thrombin generation. Pharmacological inhibition of FXII activity prolonged the time to form fibrin and increased the degree of heterogeneity of fibrin, resulting in fibrin clots with reduced mechanical properties. Taken together, this study demonstrates a dependency of the physical biology of fibrin formation on activation of the contact pathway of coagulation.

    more » « less
  2. Uncontrolled bleeding is a major problem in trauma and emergency medicine. While materials for trauma applications would certainly find utility in traditional surgical settings, the unique environment of emergency medicine introduces additional design considerations, including the need for materials that are easily deployed in austere environments. Ideally, these materials would be available off the shelf, could be easily transported, and would be able to be stored at room temperature for some amount of time. Both natural and synthetic materials have been explored for the development of hemostatic materials. This review article provides an overview of classes of materials used for topical hemostats and newer developments in the area of injectable hemostats for use in emergency medicine. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 24 is June 2022. Please see for revised estimates. 
    more » « less
  3. Abstract Background

    Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles.


    The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses.


    Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires.


    Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences.

    Trial RegistrationThis is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

    more » « less
  4. Fluid resuscitation is an integral part of critical care for burn injury patients where the necessary infusion rate is determined based on patient’s urinary output (UO). Motivated by an increasing interest in model-based development and in silico testing of automated burn resuscitation algorithms, we are investigating mathematical modeling of hemodynamic responses to burn injury and resuscitation. The model consists of 3 main components: (1) multi-compartmental volume kinetics including vascular and interstitial fluids and the associated flow interactions, (2) burn-induced hemodynamic perturbation including alterations in tissue permeability and compliance as well as denaturation with protein release, and (3) renal regulatory function including glomerular filtration rate as a function of intravascular volume state and reabsorption function representing the UO dependence on vasopressin. Preliminary evaluation of the initial model with data collected from animals show that the model can reproduce general trend of hemodynamic responses anticipated from burn injury and resuscitation. 
    more » « less
  5. Key points

    Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma, including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss.

    Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain

    Losartan, an angiotensin‐receptor blocker with anti‐fibrotic abilities, recapitulates the effect of exercise on post‐injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury


    Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients, although when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise as a result of immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioural measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microcomputed tomagraphic scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing ‘late’ (weeks 1–2) rather than ‘early’ (weeks 0–1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short‐term benefit in reducing callus volume. Providing the anti‐fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies.

    more » « less