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Restorative Cell Therapy
Restorative cell therapy is a rapidly developing, interdisciplinary field that is transforming healthcare by translating fundamental science into a variety of products and solutions aimed at repairing, regenerating, or replacing function loss caused by injury, disease, or aging. Technologies in this field encompass a variety of therapeutic approaches, including tissue engineering, cell-based therapies, gene therapy, small molecules and biologics, stem cells, and biobanking. Any combination of these technologies may be used to harness or stimulate the body’s innate healing ability in order to treat a wide range of ailments, including oncology diseases, musculoskeletal-related conditions, cardio- and peripheral vascular diseases, neurological disorders, stroke, non-healing wounds, and ocular diseases.
Articular Cartilage Repair
Articular, or joint, cartilage covers the ends of bones and allows for joints to glide smoothly with minimal friction. Cartilage damage, or chondral defects, can be caused by acute trauma, such as a bad fall or sports-related injury, or by repetitive trauma, such as general wear over time. Unlike other tissues in the body, joint cartilage has no innate ability to repair itself, making any injury permanent. Left untreated, knee cartilage damage can deteriorate into debilitating osteoarthritis and chronic pain, ultimately necessitating a joint replacement procedure.
Over 500,000 knee cartilage procedures are performed annually in the United States, primarily in the form of debridement, microfracture, conventional autologous chondrocyte implantation (ACI), and osteochondral grafting. Debridement and microfracture procedures are the most frequently performed surgical procedures for the treatment of cartilage damage, accounting for an estimated 90% of all such procedures according to research and materials from a 2009 meeting of the Cellular Tissue and Gene Therapies Advisory Committee of the FDA.
Debridement is an arthroscopic procedure that involves the removal of injured or loose tissue debris but does not attempt to repair cartilage damage. Debridement surgery typically reduces pain symptoms but does not repair cartilage damage.
Microfracture is considered the current standard of care for chondral defects due to its ability to improve symptoms in specific types of patients, its simplicity, its safety profile, and the lack of other viable alternatives. However, microfracture has been unsuccessful in reliably solving the underlying problem of cartilage damage because the repair tissue formed by the procedure is often fibrous cartilage or scar tissue, that is incapable of withstanding the typical shock and shear forces that joint cartilage sustains.
In addition to its inability to solve the underlying problem – damage to the articular cartilage – microfracture is associated with numerous other drawbacks and limitations, including the following:
- Modest and Variable Efficacy
- Limited Long-Term Patient Benefits
- Extended Patient Recovery
ACI and osteochondral grafting are procedures generally reserved either for patients who have failed prior cartilage procedures or those with extensive cartilage defects. While studies indicate beneficial outcomes for patients receiving these treatments, both have drawbacks and limitations similar to those affecting debridement and, and also are associated with the following:
- Technically Demanding Surgeries
- Negative Safety Profile
- Two-year clinical endpoints
Histogenic’s Cell Therapy Platform
To address these challenges, Histogenics developed its Restorative Cell Therapy (RCT) platform; comprising of innovative bioengineering, advanced proprietary materials sciences as well as molecular and cellular biology technologies that can be utilized individually or in a variety of combinations. Specifically, the Company’s RCT platform includes Cell Processing, Three-Dimensional Scaffolds (Biomaterials), Tissue Engineering, and Bioadhesives. With this innovative platform, Histogenics can leverage this technology and its long history of manufacturing capabilities to develop NeoCart for indications such as the repair of cartilage defects in the ankle and hip and knee.
NeoCart combines breakthroughs in bio-engineering and cell processing to enhance the autologous cartilage repair process. The restorative cell therapy merges a patient’s own cells with a fortified three-dimensional scaffold designed to accelerate healing and reduce pain. Patients then receive functional living cartilage at the time of treatment. NeoCart’s ability to function like cartilage upon implantation with its proprietary bioadhesive may allow earlier weight-bearing and return to activities.
The NeoCart autologous cell processing takes place in three phases, which occur over approximately six to eight weeks.
- Cell collection – The process begins during a short, simple arthroscopic examination when an orthopedic surgeon takes a cartilage biopsy from a non-weight bearing cartilage surface of the patient’s femur at the time of the initial diagnosis. The tissue biopsy is sent to the Histogenics manufacturing facility for culturing and expansion.
- Tissue production – The cartilage cells, or chondrocytes, are isolated from the cartilage and multiplied using standard tissue culture techniques. The cells are harvested, seeded into a unique 3-dimensional collagen scaffold, and cultured under exacting conditions of high pressure, oxygen concentration, and perfusion in its proprietary Tissue Engineering Processor (TEP). This incubation environment helps to ensure that the chondrocyte phenotype is maintained, and the cells are producing extracellular matrix proteins crucial to cartilage function prior to implantation.
- Implant – After a few weeks, a discrete three-dimensional piece of the patient’s own neocartilage, potentially having characteristics of maturing native articular cartilage, is sent to the physician and implanted into the defect using bioadhesive in a simple procedure that usually takes less than thirty minutes. Within months, there is potential for the matrix to remodel, for the cells to mature, and for the cartilage to integrate with the host tissue.
The Supply Chain Challenge
As the Company began clinical trials for NeoCart, it also began development on its proprietary Tissue Engineering Processor (TEP), which would be used to incubate the cells and grow the NeoCart product. The TEP product was developed as a static culture container with stringent material composition, dimensional, filtration, cleanliness, and quality control requirements. Histogenics recognized the need to design and build its proprietary TEP system as it could not find an adequate off the shelf product. While off the shelf containers would work during early-stage development, they presented clear challenges for the Company in the long term. Boyd Technologies worked with the Company through the patent process to ensure the protection of intellectual property was maintained.
In addition to establishing the necessary controls for a commercial biotechnology supply chain, the Company also needed a specific composition and had several specific functionality requirements. Knowing this, Histogenics sought a manufacturing partner for the production and assembly of their TEP container to support them through clinical trials and in bringing their novel restorative cell therapy to market. Due to the highly regulated nature of process aids that culture implantable cell media, it was of the utmost importance that the device was designed appropriately and manufactured, assembled, and packaged in a clean environment. Furthermore, the supply chain would need to satisfy all of the quality and regulatory requirements of the Biotechnology industry.
Building the Solution
Histogenics selected our development services platform to manufacture NeoCart process aid prototypes in support of their clinical trials. This service ranged from developing specifications, SOPs, and test methods; through validation and qualification of new equipment lines; and, finally, preparation for release to production in an ISO Class 7 cleanroom.
The integral parts of the container first needed to be cleaned in a chamber through static neutralization, high velocity compressed air, and advanced filtration. This is performed inside a Class 7 Cleanroom to minimize particulate and bioburden of the culture container. A membrane is then sealed to the lid; the parts are assembled, and the unit is packaged prior to sterilization.
Three custom equipment lines were evaluated, installed, and validated based on the performance requirements for the TEP container. Edge of Failure (EOF) trials were performed to determine the outer limits of the product specification. Design of Experiments (DOE) trials were conducted in order to optimize the process into the center of the specification. These required tests establish the operating parameters, and create the most efficient process to manufacture products that meet the acceptance criteria. For the NeoCart, a film-to-rigid peel test was performed per ASTM F-88 using in-house testing equipment. This was to ensure the bond between the membrane and TEP container lid met user inputs. Film-to-film peel tests and dye penetration tests were also performed on both layers of packaging seals to prove the integrity of the packaging barrier.
Collaborating iteratively with Histogenics’ product team, made improvements to the design based on feedback following the clinical trials. After one clinical trial, Histogenics determined the membrane did not create the most optimal cell culture growth conditions. They engaged with our material sourcing team to identify a specialized material impermeable to gases and water vapor that could be sealed to the lid in lieu of the membrane. While it didn’t need to be biocompatible as it was not in contact with the growth media, it did need to be medical grade and stable to gamma radiation for sterilization. We quickly identified a barrier film that met Histogenics’ requirements using our proprietary material database, Sourcebook®. Proof of concept samples could be manufactured and tested before launching the next phase of clinical trials.
Histogenics sought a partner to support them through several phases of clinical trials while protecting the intellectual property of their patented cell culture container. Incorporating feedback from the trials, our engineering team made changes and improvements through an iterative design process phase. Our team evaluated, installed, and validated three equipment lines in our ISO Class 7 cleanroom. We developed testing protocols and provided documentation to facilitate Histogenics’ regulatory filings throughout the product development process, supporting Histogenics as they moved away from an off-the-shelf, multi-use product to a container specifically designed for the task at hand, with appropriate documentation and change controls necessary for a biotechnology supply chain.