At Issue

At Issue: Stem cell therapy

Is there one tendon, ligament, muscle or cartilage injury that stands to benefit the most from stem cell therapy?

Autologous stem cells may improve cartilage regenerative procedures

Articular cartilage stands to benefit the most from stem cell therapy. While stem cells have been identified in nearly every human tissue, articular cartilage contains few regenerative cells. Cartilage is avascular and is devoid of a perivascular (pericyte) stem cell population, so when injury occurs, there is little response from the cartilage tissue itself. Migrating synovial cells may contribute to the body’s often-inadequate healing response.

Jason L. Dragoo, MD
Jason L. Dragoo

Although it is widely believed progenitor cells act mainly via paracrine signaling to control the local tissue environment, articular cartilage regenerative procedures will likely require the addition of stem cells (more appropriately termed “progenitor cells”) that will actually be incorporated into the repair. Augmentation of cartilage repair with autologous stem cells may improve the cell content in the regenerate cartilage and aid in extracellular matrix production. In addition, grafting techniques that use a combination of progenitor cells and chondrocytes may create a co-culture effect, where the chondrocytes supply the necessary signaling to induce the progenitor cells into the chondrocyte lineage.

At Stanford University, we are testing the hypothesis that improved cellularity resulting from autologous progenitor cell grafting will substantially improve the quality of cartilage repair with our current human, randomized clinical trials. We are comparing the results of treating isolated chondral defects with autologously harvested adipose-derived progenitor cells vs. microdrilling (modified microfracture). Another ongoing double-blind randomized controlled trial is evaluating standard surgical debridement vs. debridement plus injection autologously harvested adipose-derived progenitor cells for the treatment of symptoms of osteoarthritis. Yet another trial is evaluating the fate of the progenitor cells to determine if the injected cells in the knee are actually incorporated into the cartilage repair or just supply the necessary messaging to control the repair process. The volume and quality of the regenerate cartilage will also be measured via functional MRI scanning in each of these trials.

Evaluating the results of the level-1 trials will truly help us understand the benefit of cellular therapy for cartilage regeneration procedures.

Disclosure: Dragoo reports he is a paid consultant for Beckman Dickenson, Zimmer Biomet, Breg, CONMED Linvatec, DePuy Synthes, DJ Orthopedics, Flexion Therapeutics, Genzyme, Harvest Technologies, Joint Restoration Foundation, KCRN, Moximed, Ossur, Regeneration Technologies Inc., RNL Bio, Sideline Sports Docs LLC; he receives research support from CONMED Linvatec, Ossur, RTI and Zimmer Biomet; he receives other financial or material support from Emcyte, Harvest Technologies and RTI; and he is a paid presenter or speaker for Ossur.

ACL reconstruction, complex cartilage cases can benefit from stem cell therapy

Adam William Anz, MD
Adam William Anz

Stem cell therapies will eventually impact almost everything we do as practitioners. It is impossible to identify one big winner, but it is possible to predict which indications will win first. Current cartilage technologies have not proven they can consistently handle cases that involve large, multiple cartilage lesions. Additionally, the length of time required for graft ligamentization after reconstruction is an area where ACL techniques have stalled for 30 years. A treatment for complex cartilage cases and the improved biology of ACL reconstruction will emerge as seeing the quickest benefits of emerging stem cell therapies.

Stem cell technologies to treat cartilage injury have 40 years of developmental work behind them. Cultured bone marrow aspirate cells were differentiated into multiple tissues, including chondrocytes, adipocytes and osteocytes in the late 1970s. This later translated to animal studies in the early 1990s. Wakitani and colleagues implanted bone marrow-cultured mesenchymal stem cells (MSCs) on a collagen gel in a cartilage defect in a rabbit model. By the second week after implantation the cells differentiated into chondrocytes. By the 24th week, the tissue organized into cartilage tissue and a subchondral bone plate redeveloped.

Human clinical trials began in the late 1990s. A systematic review of human stem cell trials of cartilage repair found 60 published clinical studies, including case reports and series, 13 comparative trials and seven randomized controlled studies. In general, stem cell treatments for cartilage repair have been safe and effective, but they require further refinement through well-designed comparative study. Varying approaches are being developed, but regulatory bodies are important to ensure the proof of safety and efficacy. In the next decade, we will most likely see multiple technologies pass through regulatory pathways, develop the logistics for widespread use and be available for patient care.

One technology to monitor is mobilized hematopoietic stem cells, which has progressed to multicenter U.S. trials. Once this is approved for cartilage, it may potentially be applied to other orthopedic indications. A second technology to monitor, which is in trials now in Japan, involves a scaffold-free tissue-engineered construct derived from synovial MSCs. The extensive animal and benchtop studies underway and the unmet clinical need has set the stage for complex cartilage injuries to benefit greatly in the future.

ACL autograft wrapped with collagen matrix
Current randomized controlled trial comparing an ACL autograft wrapped with collagen matrix prior to implantation (A) then injected with bone marrow aspirate concentrate (B) at the time of implantation compared to standard reconstruction with MRI T2 mapping. Image C represents a sagittal image of the intervention group at 3 months.

Source: Adam William Anz, MD

Adjunct for graft ligamentization

The pressure of returning to play after ACL reconstruction some athletes face, and its challenges, has led to growth in the field of ACL rehabilitation in the past 15 years despite our inability to guide mother nature during graft ligamentization. The ligamentization process is variable. Human studies show graft maturation occurs between 6 and 36 months. This biologic variability is a problem for athletes who attempt a comeback and for clinicians who must restrain the zealous progress of type-A patients. Biology is the next big improvement in ACL surgery — the potential to reinvestigate ACL repair or improve graft ligamentization. We must consistently get ligamentization of autografts to occur in 6 months or less with a biologic adjunct followed by the consistent ligamentization of allografts. The future may see grafts wrapped in a collagen matrix with an injected autologous cell product at the time of reconstruction. Comparative studies are first needed to develop these concepts. Determining the best scaffold and source of cells will be the fun part of the next 10 years of ACL research.

Pyramid of evidence needed

Regardless of the indication focused on, progress will involve developing a pyramid of evidence with clinical application at the pinnacle, not at the base. Unless technologies are required to prove themselves through a well-designed process, claims of efficacy may be elusive. We must keep these new technologies on a well-thought-out, scientific, developmental path and not let them be overshadowed by cash profit and unsubstantiated claims. We should continue to build a pyramid of evidence starting with benchtop/animal studies and then followed by case series and well-designed comparative trials. By soundly developing these technologies, we can stay ahead of offering unfounded treatments for high costs. The internet needs to see more studies posted on clinicaltrials.gov and fewer websites that promote unsubstantiated medical treatments.

Disclosure: Anz reports he receives research support from Arthrex, Emcyte and KLSMC Stem Cells; and he is a consultant and speaker for Arthrex.

Human stem cells show promise in avascular necrosis therapy

Shane A. Shapiro, MD
Shane A. Shapiro

The field of orthopedics is primarily concerned with MSCs because they can differentiate into tissues within the musculoskeletal system. Advances using stem cells have already been reported for healing of avascular necrosis of the femoral head and meniscal tears. Investigations of MSCs are ongoing to treat a range of musculoskeletal conditions from ACL tears and articular cartilage lesions to degenerated intervertebral discs and partial-thickness rotator cuff tears. Cell therapy for orthopedic conditions either involves bone and joint disorders or soft tissue disorders.

A wide range of stem cell and stem cell-like products are being studied. Lumping all uses of cell therapy under the label of “stem cells” complicates our understanding of such treatments and muddies the field. Products categorized as stem cell therapies have diverse tissue origins. Fat and bone marrow are the most common sources of stem cells and products can range from “point-of-care” lower-dose products, such as bone marrow aspiration and concentration (BMAC), to ex vivo-expanded products that contain millions of cells. We characterized a standard point-of-care marrow-concentrating procedure with FDA-accepted markers using flow cytometry and found it contained less than 100,000 total MSCs whereas pharmaceutically manufactured cells used in a meniscal tear trial contained 150 million MSCs. Additionally, lower dose point-of-care therapies tend to be heterogenous cell populations with varying percentages of MSCs and numerous accompanying growth factors and cytokines, while cells that are expanded in quantity in a laboratory or manufacturing facility will be of greater homogeneity and purity. Finally, cells of any quantity may be autologous (from the patient) or allogeneic (from healthy donors).

Bone, cartilage disorders

In orthopedics, cell-based techniques have been reported as an adjunct to surgical procedures or as isolated interventions. Early clinical trials favor the efficacy of stem cell therapy for bone and cartilage disorders over soft tissue indications. Articular cartilage lesions have low vascularity, poor innate repair capability and can lead to osteoarthritis. Successful cell therapies thus far have resulted in pain relief and improvement in function with some limited early studies also demonstrating improvement in MRI appearance, as well as histological samples. Investigators have reported improvements using cell therapies for cartilage disorders irrespective of the administration protocol or cell source (bone marrow vs. fat). Mechanisms of action are still unclear, but significant quantities of growth factors, chemokines and cytokines identified in even low-dose stem cell products have been shown to promote chondrogenesis in vitro. Therefore, there is reason to be optimistic these treatments will also lead to meaningful clinical improvements in longer term studies.

Avascular necrosis (AVN) of the femoral head, like articular cartilage disorders, has traditionally been difficult to treat. In early stage pre-collapse AVN, repair of the bone has been possible after minimally invasive core decompression, but that is usually incomplete. Lack of adequate substitution of cells for bone remodeling in osteonecrotic femoral heads is now routinely being addressed by the addition of stem cells. Several prospective studies now use BMAC as an adjuvant to core decompression in early-stage AVN demonstrating improved healing of bone and decreased progression to end-stage collapse/subsequent total hip replacement. Other efforts are underway to investigate cell therapy used for AVN in the knee.

Stem cell work in ligament tears

Unlike bone and joint disorders, few studies have yet to report any strong effect of stem cells on tendons and ligaments. Limited studies of stem cell use for patellar tendinopathy, lateral epicondylitis or rotator cuff tears as an adjunct to surgical repair show promise in pain relief or healing, however, these lack adequate controls and have only level-4 evidence. Consequently, MSCs to treat ligament tears and tendinopathies have a long way to go to catch up to the favorable evidence that is mounting for bone and cartilage disorders. Fortunately, a handful of FDA-monitored clinical trials are ongoing for the use of MSCs to treat both ligament and cartilage disorders.

MSCs and associated biologically active factors
Represented in this illustration are MSCs and associated biologically active factors that contribute to bone healing as an adjunct to core decompression for AVN of the femoral head.

Source: Mayo Clinic

As the field matures, we are working on standardizing treatment protocols and accumulating evidence of safety for many stem cell products, as no major adverse events related to therapies or harvesting procedures have been reported. We are fortunate the FDA recently clarified its regulatory oversight of stem cell therapy which provides increased stability to the field. Thus, with demonstrable safety and mounting evidence of efficacy for some conditions, there is the potential to treat nearly all orthopedic disease with cell therapy. For now, we must allow the science to catch up to our enthusiasm.

Disclosure: Shapiro reports no relevant financial disclosures.

Autologous stem cells may improve cartilage regenerative procedures

Articular cartilage stands to benefit the most from stem cell therapy. While stem cells have been identified in nearly every human tissue, articular cartilage contains few regenerative cells. Cartilage is avascular and is devoid of a perivascular (pericyte) stem cell population, so when injury occurs, there is little response from the cartilage tissue itself. Migrating synovial cells may contribute to the body’s often-inadequate healing response.

Jason L. Dragoo, MD
Jason L. Dragoo

Although it is widely believed progenitor cells act mainly via paracrine signaling to control the local tissue environment, articular cartilage regenerative procedures will likely require the addition of stem cells (more appropriately termed “progenitor cells”) that will actually be incorporated into the repair. Augmentation of cartilage repair with autologous stem cells may improve the cell content in the regenerate cartilage and aid in extracellular matrix production. In addition, grafting techniques that use a combination of progenitor cells and chondrocytes may create a co-culture effect, where the chondrocytes supply the necessary signaling to induce the progenitor cells into the chondrocyte lineage.

At Stanford University, we are testing the hypothesis that improved cellularity resulting from autologous progenitor cell grafting will substantially improve the quality of cartilage repair with our current human, randomized clinical trials. We are comparing the results of treating isolated chondral defects with autologously harvested adipose-derived progenitor cells vs. microdrilling (modified microfracture). Another ongoing double-blind randomized controlled trial is evaluating standard surgical debridement vs. debridement plus injection autologously harvested adipose-derived progenitor cells for the treatment of symptoms of osteoarthritis. Yet another trial is evaluating the fate of the progenitor cells to determine if the injected cells in the knee are actually incorporated into the cartilage repair or just supply the necessary messaging to control the repair process. The volume and quality of the regenerate cartilage will also be measured via functional MRI scanning in each of these trials.

Evaluating the results of the level-1 trials will truly help us understand the benefit of cellular therapy for cartilage regeneration procedures.

Disclosure: Dragoo reports he is a paid consultant for Beckman Dickenson, Zimmer Biomet, Breg, CONMED Linvatec, DePuy Synthes, DJ Orthopedics, Flexion Therapeutics, Genzyme, Harvest Technologies, Joint Restoration Foundation, KCRN, Moximed, Ossur, Regeneration Technologies Inc., RNL Bio, Sideline Sports Docs LLC; he receives research support from CONMED Linvatec, Ossur, RTI and Zimmer Biomet; he receives other financial or material support from Emcyte, Harvest Technologies and RTI; and he is a paid presenter or speaker for Ossur.

PAGE BREAK

ACL reconstruction, complex cartilage cases can benefit from stem cell therapy

Adam William Anz, MD
Adam William Anz

Stem cell therapies will eventually impact almost everything we do as practitioners. It is impossible to identify one big winner, but it is possible to predict which indications will win first. Current cartilage technologies have not proven they can consistently handle cases that involve large, multiple cartilage lesions. Additionally, the length of time required for graft ligamentization after reconstruction is an area where ACL techniques have stalled for 30 years. A treatment for complex cartilage cases and the improved biology of ACL reconstruction will emerge as seeing the quickest benefits of emerging stem cell therapies.

Stem cell technologies to treat cartilage injury have 40 years of developmental work behind them. Cultured bone marrow aspirate cells were differentiated into multiple tissues, including chondrocytes, adipocytes and osteocytes in the late 1970s. This later translated to animal studies in the early 1990s. Wakitani and colleagues implanted bone marrow-cultured mesenchymal stem cells (MSCs) on a collagen gel in a cartilage defect in a rabbit model. By the second week after implantation the cells differentiated into chondrocytes. By the 24th week, the tissue organized into cartilage tissue and a subchondral bone plate redeveloped.

Human clinical trials began in the late 1990s. A systematic review of human stem cell trials of cartilage repair found 60 published clinical studies, including case reports and series, 13 comparative trials and seven randomized controlled studies. In general, stem cell treatments for cartilage repair have been safe and effective, but they require further refinement through well-designed comparative study. Varying approaches are being developed, but regulatory bodies are important to ensure the proof of safety and efficacy. In the next decade, we will most likely see multiple technologies pass through regulatory pathways, develop the logistics for widespread use and be available for patient care.

One technology to monitor is mobilized hematopoietic stem cells, which has progressed to multicenter U.S. trials. Once this is approved for cartilage, it may potentially be applied to other orthopedic indications. A second technology to monitor, which is in trials now in Japan, involves a scaffold-free tissue-engineered construct derived from synovial MSCs. The extensive animal and benchtop studies underway and the unmet clinical need has set the stage for complex cartilage injuries to benefit greatly in the future.

ACL autograft wrapped with collagen matrix
Current randomized controlled trial comparing an ACL autograft wrapped with collagen matrix prior to implantation (A) then injected with bone marrow aspirate concentrate (B) at the time of implantation compared to standard reconstruction with MRI T2 mapping. Image C represents a sagittal image of the intervention group at 3 months.

Source: Adam William Anz, MD

PAGE BREAK

Adjunct for graft ligamentization

The pressure of returning to play after ACL reconstruction some athletes face, and its challenges, has led to growth in the field of ACL rehabilitation in the past 15 years despite our inability to guide mother nature during graft ligamentization. The ligamentization process is variable. Human studies show graft maturation occurs between 6 and 36 months. This biologic variability is a problem for athletes who attempt a comeback and for clinicians who must restrain the zealous progress of type-A patients. Biology is the next big improvement in ACL surgery — the potential to reinvestigate ACL repair or improve graft ligamentization. We must consistently get ligamentization of autografts to occur in 6 months or less with a biologic adjunct followed by the consistent ligamentization of allografts. The future may see grafts wrapped in a collagen matrix with an injected autologous cell product at the time of reconstruction. Comparative studies are first needed to develop these concepts. Determining the best scaffold and source of cells will be the fun part of the next 10 years of ACL research.

Pyramid of evidence needed

Regardless of the indication focused on, progress will involve developing a pyramid of evidence with clinical application at the pinnacle, not at the base. Unless technologies are required to prove themselves through a well-designed process, claims of efficacy may be elusive. We must keep these new technologies on a well-thought-out, scientific, developmental path and not let them be overshadowed by cash profit and unsubstantiated claims. We should continue to build a pyramid of evidence starting with benchtop/animal studies and then followed by case series and well-designed comparative trials. By soundly developing these technologies, we can stay ahead of offering unfounded treatments for high costs. The internet needs to see more studies posted on clinicaltrials.gov and fewer websites that promote unsubstantiated medical treatments.

Disclosure: Anz reports he receives research support from Arthrex, Emcyte and KLSMC Stem Cells; and he is a consultant and speaker for Arthrex.

PAGE BREAK

Human stem cells show promise in avascular necrosis therapy

Shane A. Shapiro, MD
Shane A. Shapiro

The field of orthopedics is primarily concerned with MSCs because they can differentiate into tissues within the musculoskeletal system. Advances using stem cells have already been reported for healing of avascular necrosis of the femoral head and meniscal tears. Investigations of MSCs are ongoing to treat a range of musculoskeletal conditions from ACL tears and articular cartilage lesions to degenerated intervertebral discs and partial-thickness rotator cuff tears. Cell therapy for orthopedic conditions either involves bone and joint disorders or soft tissue disorders.

A wide range of stem cell and stem cell-like products are being studied. Lumping all uses of cell therapy under the label of “stem cells” complicates our understanding of such treatments and muddies the field. Products categorized as stem cell therapies have diverse tissue origins. Fat and bone marrow are the most common sources of stem cells and products can range from “point-of-care” lower-dose products, such as bone marrow aspiration and concentration (BMAC), to ex vivo-expanded products that contain millions of cells. We characterized a standard point-of-care marrow-concentrating procedure with FDA-accepted markers using flow cytometry and found it contained less than 100,000 total MSCs whereas pharmaceutically manufactured cells used in a meniscal tear trial contained 150 million MSCs. Additionally, lower dose point-of-care therapies tend to be heterogenous cell populations with varying percentages of MSCs and numerous accompanying growth factors and cytokines, while cells that are expanded in quantity in a laboratory or manufacturing facility will be of greater homogeneity and purity. Finally, cells of any quantity may be autologous (from the patient) or allogeneic (from healthy donors).

Bone, cartilage disorders

In orthopedics, cell-based techniques have been reported as an adjunct to surgical procedures or as isolated interventions. Early clinical trials favor the efficacy of stem cell therapy for bone and cartilage disorders over soft tissue indications. Articular cartilage lesions have low vascularity, poor innate repair capability and can lead to osteoarthritis. Successful cell therapies thus far have resulted in pain relief and improvement in function with some limited early studies also demonstrating improvement in MRI appearance, as well as histological samples. Investigators have reported improvements using cell therapies for cartilage disorders irrespective of the administration protocol or cell source (bone marrow vs. fat). Mechanisms of action are still unclear, but significant quantities of growth factors, chemokines and cytokines identified in even low-dose stem cell products have been shown to promote chondrogenesis in vitro. Therefore, there is reason to be optimistic these treatments will also lead to meaningful clinical improvements in longer term studies.

PAGE BREAK

Avascular necrosis (AVN) of the femoral head, like articular cartilage disorders, has traditionally been difficult to treat. In early stage pre-collapse AVN, repair of the bone has been possible after minimally invasive core decompression, but that is usually incomplete. Lack of adequate substitution of cells for bone remodeling in osteonecrotic femoral heads is now routinely being addressed by the addition of stem cells. Several prospective studies now use BMAC as an adjuvant to core decompression in early-stage AVN demonstrating improved healing of bone and decreased progression to end-stage collapse/subsequent total hip replacement. Other efforts are underway to investigate cell therapy used for AVN in the knee.

Stem cell work in ligament tears

Unlike bone and joint disorders, few studies have yet to report any strong effect of stem cells on tendons and ligaments. Limited studies of stem cell use for patellar tendinopathy, lateral epicondylitis or rotator cuff tears as an adjunct to surgical repair show promise in pain relief or healing, however, these lack adequate controls and have only level-4 evidence. Consequently, MSCs to treat ligament tears and tendinopathies have a long way to go to catch up to the favorable evidence that is mounting for bone and cartilage disorders. Fortunately, a handful of FDA-monitored clinical trials are ongoing for the use of MSCs to treat both ligament and cartilage disorders.

MSCs and associated biologically active factors
Represented in this illustration are MSCs and associated biologically active factors that contribute to bone healing as an adjunct to core decompression for AVN of the femoral head.

Source: Mayo Clinic

As the field matures, we are working on standardizing treatment protocols and accumulating evidence of safety for many stem cell products, as no major adverse events related to therapies or harvesting procedures have been reported. We are fortunate the FDA recently clarified its regulatory oversight of stem cell therapy which provides increased stability to the field. Thus, with demonstrable safety and mounting evidence of efficacy for some conditions, there is the potential to treat nearly all orthopedic disease with cell therapy. For now, we must allow the science to catch up to our enthusiasm.

Disclosure: Shapiro reports no relevant financial disclosures.