Biomfg

Biomanufacturing for Regenerative Medicine

The Joint Program Committee (JPC)‐8/Clinical Rehabilitative Medicine Research Program (CRMRP), Defense Health Agency (DHA) J‐9 R&D Directorate, and Office of the Assistant Secretary of Defense for Health Affairs (OASD(HA)) have identified a need for regenerative medicine prototype development efforts and manufacturing technologies.

Current Good manufacturing practice (cGMP) quality is a requirement by the FDA and European Medicines Agency to provide patients with clinical‐grade products that are safe and have defined quality characteristics. However, standardization and robust manufacturing techniques are lacking in regenerative medicine, which will continue to impede progress in advancing regenerative medicine based technologies and treatments toward the clinic.

Based on this, the major objective of this program is to develop scalable, production‐ready, commercial prototypes and processes for cell, tissue, or organ bioengineering technologies that will overcome current challenges and enable successful cGMP manufacturing and clinical translation of regenerative medicine based therapies. Technologies of interest included:

  1. 1. Bioreactors to enable efficient and cost‐effective cell and tissue expansion for regenerative medicine products
  2. 2. Cell, tissue, and product preservation for regenerative and personalized medicine
  3. 3. Large scale manufacturing and quality assurance of regenerative medicine‐ based products
  4. 4. Dynamic and innovative quality assurance strategy for regenerative medicine manufacturing

This RPP was a follow‐on effort to MTEC’s previous (2016) Regenerative Medicine Manufacturing 16-02-RegenMed, where several technologies of interest were previously funded. The research project award recipients were selected from the Offerors who responded to MTEC’s Request for Project Proposals (19-07-Biomfg).


Title of Project: A Novel Perfusion-Based, Scalable, and Single-Use Cell Expansion Bioreactor – Advanced Development and Demonstration in a Clinical Cell Manufacturing Environment
Project Team : Southwest Research Institute, GenCure, RoosterBio, US Army Institute of Surgical Research
Award Amount:  $2,948,354
Project Duration: 3 years
Project Objective: Advanced regenerative medicine therapies are exciting research topics, with more than 800 stem cell therapies currently in clinical trials. For these procedures, doctors either replace diseased or ineffective stem cells with healthy new stem cells or use stem cells as a “living drug” for the treatment of diseases like diabetes, traumatic brain injuries, and Alzheimer’s and Parkinson’s diseases. The cells can also be used to treat spinal cord injuries, heart disease and wounds. However, the promise of personalized, regenerative medicine is limited, in part, by scale. For example, only about 100,000 cells with regenerative potential can be harvested from a donor, but effective treatments often require a billion cells for a single dose, requiring a 10,000-fold increase for clinical applications. Existing technologies do not meet the practical clinical needs for cell manufacturing. The current cell manufacturing typically requires an expensive, labor-intensive cell culture process in high-cost cleanroom conditions, while often reduced the function of the stem cells.

The objective of this project is to advance the fabrication process of a new cell manufacturing platform using a perfusion-based and scalable bioreactor system, and demonstrate its applications in human bone-marrow mesenchymal stem cells expansion and exosome production in a clinical cell manufacturing environment. The over-arching goal of the project is to develop an automated, turnkey, standalone perfusion system together with single-use bioreactors. This system is expected to simplify the stem cell manufacturing process, reduce the labor, reagent, and facility costs while maintaining the stem cells’ functions, and therefore, have high impact to the regenerative medicine and bring benefits to the patients.

Southwest Research Institute’s patent-pending, disk-shaped bioreactor features tightly packed, interconnected spherical voids, providing a large surface-to-volume ratio for perfusion-based, scalable manufacturing of abundant quantities of cells.

Title of Project: Development of a Universal Bioreactor Platform for Regenerative Medicine Clinical Manufacturing
Project Team: RegenMed Development Organization; Wake Forest Institute for Regenerative Medicine
Award Amount:  $3,000,000 (with additional cost share of $3,125,000)
Project Duration: 4 years
Project Objective: Tissue engineered products are fabricated by applying cells to an appropriately shaped biomaterial scaffold. Because these products are alive, specialized bioreactors are required for supplying required conditions that would normally be supplied by the host circulatory system and surrounding tissues. Currently, the regenerative medicine industry designs and fabricates custom bioreactors for each product under development. The cost and time associated with development and customization of these custom-build bioreactors are extremely high. The objective of this project is to design and fabricate a contained standardized, scalable, modular, and configurable bioreactor platform to address this need.

Components of a Standard Bioreactor Platform.

 


Title of Project: Large scale manufacturing of extracellular matrix (ECM) hydrogels for regenerative medicine applications
Project Team: University of Pittsburgh; ECM Therapeutics, Inc.
Award Amount:  $1,995,843 (with additional cost share of $213,144)
Project Duration: 2 years
Project Objective: The objective of the project is to develop scalable, production ready commercial extracellular matrix (ECM) hydrogel prototypes for use in regenerative medicine clinical applications. Using our novel method for rapid and high-yield ECM hydrogel processing, we will initially develop an ECM hydrogel formulation intended for use as a hemostatic agent. The use of a concentrated ECM hydrogel extends its use beyond routine surgical procedures to include its use in acute traumatic soft tissue injuries, bulk tumor resection, and whole organ hemorrhage. Our technical approach is supported by extensive preclinical research demonstrating the hemostatic efficacy in a rodent model of liver laceration and a canine model of volumetric muscle loss. The ECM hydrogel has several advantages over existing hemostatic products including dramatically improved ease of use, and its potential to simultaneously initiate constructive remodeling of damaged tissue via immunomodulation and stem cell recruitment. This proposal will advance ECM hydrogel production from laboratory protocols to cGMP-compatible manufacturing processes that will overcome current challenges in ECM hydrogel production and enable clinical translation of this next generation regenerative medicine-based therapy.

(A) ECM hydrogels, (B) lyophilized 3D ECM structures, (C) ultrathin ECM sheets, and (D) injectable hydrogel formulations