While chronically ischaemic tissues (e.g. diabetic foot ulcers, wounds resulting from limb ischaemia, burns) are constantly exposed to hypoxia, the primary stimulus for angiogenesis (i.e. formation of new blood vessels), they paradoxically appear to have a limited capacity to appropriately respond to hypoxic stress.  The mechanism underlying the inadequate generation of compensatory angiogenesis, and subsequently a satisfactory wound healing response, seen in many chronic ischaemic conditions involves a blunting of the ability of cells to increase the expression of angiogenic factors (e.g. VEGF, angiopoietins) in response to prolonged hypoxic episodes. Exposing selected cell types to hypoxia in vitro, i.e. culturing cells under wound-simulating conditions, can stimulate production of angiogenic factor proteins. Controlled delivery of such complex, yet physiological, factor mixtures in vivo could thus provide a solution to overcoming the limited ability of ischaemic tissues to optimally switch on angiogenesis. This strategy therefore aims at overriding the habituated response of cells within an ischaemic tissue, restarting the regenerative process and driving it to completion. 

In 2010 and 2011 our group reported on two strategies for delivering fibroblast-derived hypoxia-induced angiogenic signaling in vivo (Hadjipanayi et al. 2010;Hadjipanayi et al. 2011 under Publications). In 2012 we described a new injectable (i.e. minimally invasive) system for localised delivery of cell-free matrix carriers loaded with hypoxia-induced angiogenic factors (Hadjipanayi et al., 2012 under Publications). For translating this system into a therapy that can easily be used at the bed-side, we have identified peripheral blood cells (PBCs), as the ideal factor-providing canditates. In contrast to skin fibroblasts, which have to be obtained invasively through a biopsy, and need pre-expansion, PBCs are readily obtained in sufficient numbers. Also, as they are autologous, immunological/infectious adverse effects can be prevented.



 

EmaCure® is the first wound therapy employing Hypoxia Preconditioned Products (HYPPP®), autologous preparations of blood-derived wound healing factor proteins, bound within a matrix carrier. The EmaCure® therapy is prepared by conditioning PBCs under wound-simulating conditions (hypoxia, physiological temperature) outside the body (Extracorporeal Wound Simulation) for a defined period of time (typically 4 days). This approach provides a significant improvement over currently available systems for preparation of autologous blood-based compositions, such as platelet-rich plasma (PRP) gel, as it makes it possible to deliver hypoxia-induced (i.e. angiogenesis-targeting) factor mixtures of higher protein concentration and potency, rather than only the factors already present within cells (platelets) at the time of blood collection. 

The EmaCure® therapy can be delivered in the form of wound dressings  and injectable preparations, which are entirely cell-free. Since the protein factors are derived from patient autologous blood, this therapy is patient-specific. By using a personalised therapy, clinicians can then better target the wound healing process, as the growth factor requirements for an adequate wound healing response are known to show significant variablity between individuals.  It will thus have significant utility both at the bed-side, as an angiogenic therapy in peripheral ischaemic tissue such as wounds, ulcers and burns, as well as pre-, intra- and post-operatively as angiogenic support for central ischaemic tissue, grafts, and engineered implants.

The EmaCure® wound therapy is being developed by a  multi-disciplinary team of researchers, including cell biologists, engineers, clinicians and plastic surgeons, as well as specialists in translational therapy regulation. The network of collaborating institutions includes the Technical University Munich, Hochschule München, Bogenhausen Hospital Munich and University of Göttingen.

A patent application on a one-step device for preparing and delivering the EmaCure therapy was first filed in February 2012 ((PCT/EP2013/051910;''Device based methods for localized delivery of cell-free carriers with stress-induced cellular factors''). The patent was published in Aug 2013 (IPN: WO 2013/113821 A1) and finally granted in 2017.