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CareDx Transplant Rejection Assays to Help Guide Miromatrix Bioengineered Organs to Market


This story has been updated from a version posted April 4 to include additional comments from CareDx and Miromatrix.

NEW YORK – In an attempt to address an organ supply shortage in the transplant market, Eden Prairie, Minnesota-based Miromatrix Medical is developing animal-derived bioengineered organs for allografts.

To help guide these bioengineered organs to market, Miromatrix has tapped CareDx to develop allograft rejection tests for use in preclinical animal models and serve as Miromatrix's exclusive provider of donor-derived cell-free DNA testing services in human clinical studies.

Financial details of the partnership, announced Wednesday, were not disclosed.

CareDx made a minority investment in Miromatrix in 2021 and participated in that company's Series C funding round.

Miromatrix's bioengineered organs consist of medical-grade pig organs that have been decellularized using Miromatrix's proprietary technology, leaving in place the extracellular matrix with native organ structures, including vascular structures, then recellularized with human cells from organs not suitable for transplant.

"The preservation of the organ and vascular structures enable the recreation of the functional structures, and the intact vasculature ensures proper nutrients delivery," said Jeff Ross, CEO of Miromatrix.

Furthermore, each human organ the company receives can be expanded to create multiple bioengineered organs.

"Our perfusion decellularization/recellularization technology is the core of our bioengineered organ platform and is protected by 144 patents and 43 pending patents," Ross added.

CareDx did not provide details of the test to be developed for this collaboration, except to say that the assay will be designed to differentiate human DNA in a background of animal DNA.

"CareDx will develop an innovative donor-derived cell-free DNA testing solution for Miromatrix to use in preclinical models to noninvasively assess rejection," said Robert Woodward, senior VP of research and development at CareDx.

Testing throughout the preclinical stage of the collaboration will take place at CareDx's CLIA-certified R&D laboratory in Brisbane, California.

Justin Chan, a cardiovascular and thoracic surgeon and assistant professor of cardiothoracic surgery at NYU Grossman School of Medicine, mentioned that while organ biopsy or necropsy samples would likely remain the gold standard rejection assay in laboratory and animal testing phases of bioengineered organs, cfDNA "might be useful as an adjunct during the testing phase to give an idea of other forms of graft injury that we don’t anticipate, as the technology is so new and we don’t know what we don’t know."

Woodward commented that dd-cfDNA readily detects acute injury. 

"The primary concern for the graft in any new use situation is acute rejection, which causes an acute injury that is readily detected by dd-cfDNA," he said. "Earlier detection also means that interventions can be deployed to help prevent irreversible organ damage."

Ross added that a dd-cfDNA assay "would be beneficial for our bioengineered organs to detect any signs of rejection earlier and provide more time to alter therapy to ensure the best patient outcome."

Transplanting animal organs into humans, a process known as xenotransplantation, also carries with it risks of immunologic rejection and the introduction of infectious disease.

Whole-organ bioengineering has so far stayed mainly in the lab, where issues such as retaining a functional vascular network and residual exposed areas of extracellular matrix have slowed progress.

Miromatrix previously published research in Nature Biomedical Engineering, showing that it successfully revascularized decellularized pig livers with human umbilical vein endothelial cells (HUVECs) and sustained continuous blood flow in pigs for up to 15 days after transplant.

In another study published in Nature Communications Biology, the company demonstrated further functional metrics in its bioengineered livers, through the presence of albumin production, ammonia detoxification, and urea synthesis.

NYU's Chan cautioned that bioengineered organs face some stiff hurdles in proving themselves clinic-ready.

"The technology is promising but still a bit early in the development," he said. "The complexity comes from the fact that for a functional organ, many different cell types have to be placed in precise anatomical locations [and] at the microscopic level to be functional."

While Chan worries that this problem has yet to be fully solved, Miromatrix's Ross said that the company has done so and hopes to demonstrate this over future clinical studies.

"Our scientific team has identified the conditions to introduce human cells isolated from organs not placed for transplant into the decellularized matrix," he said. "Under these conditions, the human cells demonstrate the ability to reproducibly organize appropriately and display organ specific function."

Miromatrix's pipeline currently consists of one bioengineered kidney product — Mirokidney — and two bioengineered liver products, called Miroliver and MiroliverELAP, the latter developed specifically for use in dialysis in the case of acute liver failure, in collaboration with Baxter International.

Miromatrix filed an investigative new drug (IND) application for MiroliverELAP late last year and received a clinical hold letter from the US Food and Drug Administration, asking for additional information.

"We will be resubmitting our IND for MiroliverELAP in the second half of 2023," Ross said. "We envision submitting INDs for our fully implantable bioengineered organs (Mirokidney and Miroliver) after the MiroliverELAP IND is cleared by the FDA."

To that end, the company is preparing to initiate a Phase I clinical trial of MiroliverELAP at approximately eight sites. Miromatrix envisions enrolling approximately 15 patients, with a primary endpoint of survival at 48 to 72 hours and a secondary endpoint of survival at 21 days.

"Once initiated, we envision [that] the Phase I trial data could be collected in as little as six months," Ross said.

While the current products in Miromatrix's pipeline are allografts derived from healthy donor cells in otherwise transplant-unsuitable organs, the company does plan to create a "second generation" line of organs derived from a patient's own cells or from a superdonor, which would likely require much less post-transplant immunosuppression.

Miromatrix and CareDx will also have to assess for the possibility of an immune reaction against the porcine organ matrix, although Ross has pointed out in the past that Miromatrix's other products, Miromesh and Miroderm, both porcine-derived biological matrices used in wound repair, have been implanted in thousands of patients with no reported adverse reactions related to an immune response.