This article is more than 5 years old. Information may no longer be current.
Practical application of biologics: Part 2
Click Here to Manage Email Alerts
In the first part of this Orthopedics Today Round Table on the use of biologic augmentation in soft tissue healing, our panel discussed the current status and future potential of platelet-rich plasma. We also discussed current issues related to stem cells, and the limitations imposed by the current regulatory environment. In this continuation of our discussion, I have asked the panelists to address further questions that directly relate to the potential clinical use of stem cells. The panelists discuss the possibility of using various “off-the-shelf” allogeneic cell sources. The panelists also provide their thoughts about combining stem cells with scaffolds to augment tissue repair. I then finish with some concluding remarks related to biologic augmentation of soft tissue healing.
Scott A. Rodeo, MD
Moderator
Roundtable Participants
-
Moderator
- Scott A. Rodeo, MD
- New York City
- Jason L. Dragoo, MD
- Redwood City, Calif.
- Martha M. Murray, MD
- Boston
- Regis J. O'Keefe, MD, PhD
- Rochester, N.Y.
- George F. Muschler, MD
- Cleveland
Scott A. Rodeo, MD: What is the potential for “off-the-shelf” sources of progenitor cells, such as allogenic marrow-derived cells or cells derived from tissues such as placenta or amnion, for orthopedic applications?
Jason L. Dragoo, MD: It is unknown. The first step in determining the clinical potential of allograft cell sources is to perform more rigorous basic science and animal studies to determine both the number of progenitors cells contained in the commercial tissue preparations and to better establish a safety profile. Here are a few examples: How many progenitor cells are contained in commercially available amniotic fluid or tissue preparations? Answer: Nobody knows, not even the companies. Another example is fresh osteochondral allograft transplantation, where it is critical to remove all bone marrow elements to avoid an immunogenic host response. However, allograft bone graft with live bone marrow/progenitor cells has recently been FDA approved and is now available for use. Although tissue banks claim they have denatured the marrow to minimize immunogenic potential, it is unclear if this process will also denature the stem cell capacity or completely eliminate immunogenicity of the tissue.
Martha M. Murray, MD: Establishing an adequate nutritional and oxygenated environment at the site of transplantation is likely the biggest hurdle for the use of any transplanted cells, including allograft progenitor cells. Our ability to successfully use these cells in clinical care will be dependent on our ability to identify or create those environments. If that can be accomplished, there is great potential for this technology.
George F. Muschler, MD: This is a multimillion to billion dollar question. There are many cell therapy companies that have invested a huge amount of capital making the bet that culture-expanded cell populations will be essential or at least more effective than methods for point-of-service harvest and processing of autogenous cells. Allograft products can be fabricated and characterized at a fraction of the cost of culture expanding patient specific cell populations. The unanswered question is currently efficacy. What will work better, culture-expanded cells or freshly isolated cells? The best place to answer this question is in rigorous, objective and clinically relevant animal models. But this is an approach that has not yet found much traction.
If, hypothetically, the efficacy of culture-expanded cells is equal to autogenous point of service preparations, allograft cells will be preferred form a purely commercial perspective. Culture-expanded allograft cells will always be less expensive per unit dose to manufacture and deliver. Allograft cells would presumably also be more consistent and standardized. Those factors have great appeal in a regulatory environment. However, it cannot be forgotten that when compared to point of care methods, culture-expanded allograft products also carry an inevitable risk associated with lot to lot variation, in vitro senescence, the potential acquisition of (even selection for) undesirable mutations or epigenetic changes, loss of viability in storage and transportation, and episodes of compromise in batch sterility.
Regis J. O’Keefe, MD, PhD: This is a long-standing area of research. One of the major potential issues, which is largely solved, involves immune recognition and elimination of the transplanted cell populations. Progenitors from early embryonic derived tissues express lower levels of histocompatibility antigens and thus escape immune detection.
There are still numerous remaining questions. We still require evidence-based results in humans to show efficacy. We do not yet completely understand the fate of transplanted cells — Do they participate in the repair process or stimulate local cells to undergo the proliferation and differentiation necessary for regeneration? What is the best mechanism of cell delivery? Is it systemic or local? How many cells should be injected? While the potential is excellent for use of such cells clear evidence of their efficacy needs to be established.
Rodeo: Ultimately, the most efficacious biologic approaches may combine cells, chemical signaling factors and scaffolds. What is the most practical and promising option for combining scaffold materials with either cells or growth factors, such as platelet-rich plasma (PRP)?
Dragoo: A combination of an autologous cell source, biologic adjuvant (PRP) and scaffold will likely lead to the most targeted regenerative approach. However, each part of this regimen needs to be optimized prior to widespread clinical use. Otherwise, we can expect the same mediocre results attained with current PRP therapy.
Murray: The most promising constructs combine a natural scaffold (collagen, fibrin, elastin and other extracellular matrix proteins) and a source of growth factor. These types of constructs can be designed to encourage in situ cell recruitment to wound sites to augment repair of soft tissues and bone. Blood components, including whole blood or PRP, represent inexpensive sources of multiple growth factors. Platelets in particular can be stimulated physiologically by exposure to collagen in a wound site and then serve as a source of temporally controlled growth factor release. I believe whole blood, as the body’s own natural wound healing scaffold, is the most practical and promising biologic for orthopedic applications. The use of a sponge or carrier to hold the blood in the location of the desired action may also be useful, particularly in unconfined areas such as the articular joint. For example, this approach has had documented success for healing of the ACL within the knee joint in validated animal models. Whether it will also be successful in human patients requires further study.
Muschler: I agree with this premise. One can speculate about the myriad of potential combinations of cells sources, processing methods, scaffolds and signaling factors. However, ultimately speculation is silenced by data. The preferred combination will inevitably vary depending on the clinical site, setting and the systemic health of the patient. Rather than speculate, I would like to see us re-double our efforts to define and support rigorously controlled animal model systems that enable us to work through these important questions, and then translation of optimized methods into clinical trials, alone or in combination. As a patient, physician or investor, I would feel more comfortable with being involved in a clinical trial if the therapeutic strategy had first been vetted in an animal model system and had already proven itself to be the best of the available options.
O’Keefe: This is the optimal methodology, but this true tissue-engineering approach (cells, matrices and growth factors) needs to navigate challenging regulatory hurdles and will be costly. An inherent challenge is that any tissue engineered composite will be placed in humans that have different genetics, environmental exposures, disease states, and gender — all of which can modify the response. Thus, unlike animal experiments that often use genetically in-bred strains of animals, there will be a variable response among individual subjects. Finally, a challenge is that the integration of different components at various concentrations or compositions leads to a large matrix of potential products. The amounts used and the relative proportion of the different components is primarily empirically driven — different compositions are tested and the best one is selected. However, this does not mean the optimal material (cells, matrix and growth factors) is used. The bottom line is that while it seems easy and intuitive, tissue engineering is complex and has to clear the high bar set by regulatory agencies. At present, clinical use is limited to the use of individual growth factors or tissue preparations, like PRP.
Concluding thoughts
Rodeo: It is clear that cell-based approaches and cytokines, such as those contained in PRP, have significant potential for augmentation of soft tissue healing. Although there are many avenues for continued research, I believe that especially fruitful areas for further insights will come from study of developmental biology and genomics. The signaling molecules that are involved in tissue formation in embryogenesis may inform approaches to improve tissue healing and tissue regeneration.
As genomics research furthers our understanding of gene structure and function, regulation of gene expression and gene-environment interactions, we will have the ability to choose the optimal therapy for the individual patient. Such a “personalized medicine” approach could be a paradigm shift in the use of biologic therapies, since the tremendous variability in reported outcomes using modalities such as PRP and stem cells is likely due to inter-individual genetic variations. As we learn more about how to use cytokines and cells to improve tissue healing, the next frontier will be to use this knowledge for tissue regeneration and tissue engineering applications. Thus, new knowledge about basic soft tissue biology will not only aid our ability to augment tissue healing, but also tissue replacement.
Most of the research on stem cells has focused on the use of exogenous cells, either autogeneic or allogeneic. However, it is now known that there is an intrinsic stem cell niche in many tissues, including tendons, ligaments and menisci. Our next challenge is to learn how to stimulate these local, intrinsic cells to aid tissue healing. This would allow us to exploit the body’s own inherent ability for regeneration.
Lastly, further understanding of biologic approaches may suggest ways to prevent or even reverse age-related degenerative changes that occur in many tissues. It is likely that cellular senescence due to the aging process plays a critical role in the poor healing potential of orthopaedic soft tissues. If the adage “an ounce of prevention is better than a pound of cure” holds true for treatment of established disease, then perhaps early recognition and treatment of intrinsic age-related degenerative changes may allow intervention using “biologic strategies” (stem cells, PRP, cytokines, etc.) to prevent further adverse tissue changes and resultant injury and disability. Instead of treating injured tissue, perhaps we can prevent the injury or damage in the first place.
The ability to intervene in such a “preventive” fashion will be dependent upon better methods to detect pathologic changes in orthopedic soft tissues at a time when intervention may be effective. In my opinion, a critical need is for the development of accurate biomarkers of disease that will allow early detection and intervention. While cardiologists can follow serum lipids as a marker for cardiac disease and endocrinologists can follow serum glucose as a marker of diabetes, we have no similar specific biomarkers for orthopedic soft tissues. Further research is required to identify and validate chemical (in blood, urine or synovial fluid) or imaging biomarkers. Such biomarkers would not only facilitate early diagnosis, but could also provide objective methods to evaluate the response to treatment using biologic approaches. This will be an important avenue for further study if we are to realize the full potential of these emerging and exciting approaches to treatment.
For more information:
Scott A. Rodeo, MD, can be reached at Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021; email: rodeos@hss.edu.
Jason L. Dragoo, MD, can be reached at Stanford University Medical Center, Department of Orthopaedic Surgery, Division of Sports Medicine, 450 Broadway St., Pavilion A, Redwood City, CA 94063; email: jdragoo@stanford.edu.
Martha M. Murray, MD, can be reached at Children’s Hospital of Boston, Hunnewell 219 Ortho Surg, 300 Longwood Ave., Boston, MA 02115; email: martha.murray@childrens.harvard.edu.
Regis J. O’Keefe, MD, PhD, can be reached at University of Rochester Medical Center, 601 Elmwood Ave., Box 665, Rochester, NY 14642; email: regis_okeefe@urmc.rochester.edu.
George F. Muschler, MD, can be reached at Cleveland Clinic Foundation, 9500 Euclid Ave., Desk A-40, Cleveland, OH 44195; email: muschlg@ccf.org.
Disclosures: Dragoo and O’Keefe have no relevant financial disclosures; Murray receives research support from the National Institutes of Health (NIH), the National Football League Players Association, and the Children’s Hospital Orthopaedic Surgery Foundation; Muschler is a consultant to the NIH, FDA, Smith & Nephew and Fortus and receives funding from the NIH, Department of Defense, Harvest Technologies, Medtronic, Fortus and DSM Biomedical; Rodeo receives research support from the Arthroscopy Association of North America, AOSSM/MTF Meniscus Transplantation Grant and the Arthritis Foundation, and is a consultant for Rotation Medical, Cytori and Pluristem.