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ONE-STAGE CELL THERAPIES – STATE OF THE ART TECHNIQUE

– Written by Konrad Słynarski, Poland, Theodorakys Marín Fermín, Venezuela and Emmanouil Papakostas, Qatar

 

 

INTRODUCING THE VILLAINS

Epidemiology of Cartilage Injuries

Cartilage injuries are potentially harmful lesions affecting around 60% of patients undergoing knee arthroscopy1,2. Full-thickness focal defects are more frequently found in athletes and may be present in up to 59% of them3,4. The most common locations are the patellar (36%) and medial femoral condyle (34%) surfaces and are often associated with a medial meniscus tear (42%) or anterior cruciate ligament injury (36%)1. While most isolated chondral injuries are asymptomatic, they may present with pain, locking or catching sensation, swelling and/or pseudoinstability4.

 

Cartilage Healing Potential

Due to the highly specialized hyaline cartilage cells and tissue properties, its regeneration potential is low5. Additionally, the avascular nature of cartilage tissue and incapacity for clot formation hinders the main steps that occur in other tissues after an injury6,7.

Cartilage tissue attempt at healing depends on defect size and depth8. Partial-thickness cartilage injuries do not violate the subchondral bone and do not repair spontaneously5. Cell adjacent to the defect margins undergoes cell death, and chondrocytes and migrating synovial cells fail to fill the defect after an injury5,9,10.

On the other hand, the healing process after full-thickness injuries involves several cell types arising from the bone marrow after subchondral plate breaching11. In these cases, the resulting synthesized extracellular matrix after hematoma formation does not replicate the native morphology and mechanical characteristics of the native tissue but produces fibrocartilage5. This fibrocartilage tissue primarily consists of collagen I fibers with limited durability12.

Furthermore, smaller lesions may dissipate weight-bearing forces across it, protecting the subchondral bone, but larger lesions may fail to do so. In those cases, the exposed subchondral bone will become abrasive to the opposite chondral surface, creating bipolar injuries and consequent subchondral edema7,13. When untreated, these defects may progress to knee osteoarthritis5,14.

Several treatment approaches are available to address focal cartilage injuries of the knee. However, the standard treatment is yet to be defined. Non-surgical options include rehabilitation and physical therapy, and intra-articular injections15. On the other hand, surgical treatment options range from debridement and bone-marrow stimulation techniques to more complex procedures, including osteochondral autologous transplantation, osteochondral allografts, mosaicplasty, and cell-based therapies16.

 

Costs of Autologous Chondrocyte Implantation (ACI)

Knee ACI, first performed in 1994, showed promising results in managing focal cartilage injuries17. Studies have addressed its cost-effectiveness with favorable results, with cost savings related to fewer work absences and disability18. This is especially relevant in the young and active population, in which regenerative techniques potentially allow better and sustained long-term outcomes compared to other techniques19.

Everhart et al18, in their systematic review, found that matrix-induced autologous chondrocyte implantation (MACI) had better cost-efficacy than its counterpart implementing a periosteal cover, with costs surpassing 50,000 USD per quality-adjusted life-year over ten years. However, this two-stage procedure is still expensive, costing approximately 16,226 EUR20. The need for a second procedure is a difficulty that translates into additional indirect costs from loss of productivity and qualitative deleterious effects from a time and monetary point of view18.

Likewise, Its logistical complexity and the need for chondrocyte culture in highly specialized laboratories with processing costs exceeding 30,000 USD in the United States have limited its widespread implementation21,22. Since then, numerous modifications of this technique have been introduced, aiming for a single-stage definitive solution given its cost-saving potential.

 

CHOOSING THE WEAPONS

Chondrocytes: The Secluded Cell of Cartilage Tissue

Chondrocytes are mesenchymal cells specialized in extracellular matrix synthesis5. They represent only 2% of the articular cartilage volume and lead the cartilage homeostasis through secreting enzymes, growth factors, and inflammatory mediators5,7. Cartilage extracellular matrix is mainly composed of collagen II fibers, proteoglycans, and glycoproteins. The matrix interweaved architecture results in unique viscoelastic properties, providing a smooth and lubricated surface for low friction movement and load transmission5.

Chondrocytes are the only cells capable of creating new hyaline cartilage. Thus, the quest for cartilage restoration has involved its implementation in several attempts. ACI has been demonstrated to be an effective treatment option in managing large, full-thickness symptomatic chondral lesions of the femoral condyles with early improvement and sustained at long-term follow-up23,24.

Moseley et al23, in a multicenter observational study comprising 72 patients, reported that 75% of them improved from their baseline scores at 1 to 5-year follow-up, and 87% maintained their improvement to the last follow-up (mean 9.2 years), with an early failure rate in 17% of patients (mean 2.5 years). Similarly, Peterson et al24 have reported similar outcomes in 224 patients with follow-up as long as 20 years.

While first-generation ACI has demonstrated satisfactory outcomes, there is still a gap for improvement in clinical outcomes, failure rates, and costs. Current practices aim to harvest chondrocytes from non-weight-bearing cartilage zones and implement fast isolation protocols, avoiding cell culture and two-stage procedures25. Moreover, it has been suggested that implementing chondrocytes from the injury rim or even arthritic cartilage seems not to alter the quality of newly synthesized cartilage, which may help to avoid donor-site morbidity22,25.

Hyaline cartilage is harvested using a shaver or curettes from the medial margin of the medial femoral condyle, medial margin of the trochlea, or the lesion rim area to obtain approximately 0.3 g25. This tissue is recycled using enzymatic reactions to obtain chondrons (chondrocytes with their pericellular matrix) within an hour, enabling one-stage procedures. Cells are washed and counted to meet the density and ratio according to the defect17,25.

 

Bone-Marrow-Derived Mesenchymal Stem Cells (BM-MSC): The Most Popular Stem Cell

Mesenchymal stem cells (MSC) are an adult lineage of multipotent cells with the potential to differentiate to the bone, cartilage, and other connective tissues by local signaling and genetic potential at embryonic stage26,27. However, according to the current understanding all MSC are pericytes, embeded in the capillaries, and do not differentiate to other cells type, but, when activated, secret growth factors that have influence on surrounding cell types28.

Pericytes are stimulated by soluble growth factors and chemokines to become activated MSC, which respond to the microenvironment by secreting trophic (mitogenic, angiogenic, anti-apoptotic or scar reduction), immunomodulatory or antimicrobial factors28.

They are currently the most widely used stem cells29. According to the International Society for Cellular Therapy criteria30, a MSC must be (a) plastic adherent, (b) express CD105, CD73, and CD90, and not CD45, CD34, CD14, or CD11b, CD79 alpha or CD19, and HLA-DR surface molecules, and (c) differentiate into osteoblasts, adipocytes, and chondroblasts in vitro.

These cells are typically harvested in the iliac crest by aspiration, although the number of collected cells is minimal31,32. In the bone marrow of skeletally mature patients, the number of MSC ranges from 1:50000 to 1:100000, a few hundred per milliliter of marrow aspirate31. Furthermore, the implementation of allogeneic MSC has shown not to activate an adverse immune response while promoting chondrogenic potential of the surrounding chondrocytes, presenting as a safe option to be implemented.

Theoretically, the chondrogenic and trophic potential of MSC and homing are the most critical mechanisms in which these cells participate in the restoration of cartilage27,33-35. The first one, in which the cells differentiate to cartilage cells restoring the lost function and morphology; and the second, secreting several bioactive factors to promote repair environment31. The latter being the most accepted after de Windt et al17 revealed that tracking these cells showed a temporary behavior, enhancing joint homeostasis before disappearing.

In a case series by Gobbi et al21, successful comparable long-term outcomes in IKDC, KOOS, and Tegner activity scale were obtained when implementing BM-MSC in a hyaluronan-based scaffold for the treatment of full-thickness cartilage injuries ≥ 1 cm². The implementation of BM-MSC in a hyaluronan-based scaffold is an emerging therapeutic option among one-stage cartilage restorative procedures.

 

Synergistic Effect of Combined Chondrocyte and Mesenchymal Stem Cells

It has been suggested that a combination of chondrocytes and BM-MSC may increase the chondrogenic potential of the firsts36,37. Although MSC have shown no differentiation into chondrocytes in these circumstances in recent investigations17, paracrine trophic and immunomodulatory effects contribute to the regeneration of the lesion25. It seems that MSC fade over time but secreting site-specific factors that promote tissue regeneration17. Complementing chondrocytes with MSC ensures a higher cell density in the defect and stimulates further hyaline matrix synthesis25,38-41.

 

Scaffolds and Carriers

The use of scaffolds has also been widely studied during the last decades. They show advantages such as the uniform distribution of the seeded cells, provide a temporary platform for the new to be synthesized extracellular matrix which components may be implemented for such role42-44.

Hyaluronan-based scaffolds and fibrin glue are among the most popular options, but new biomaterial are being continuously developed and studied for cartilage restoration29,45-47. To date, hyaluronan-based scaffolds have shown to be superior to other types, as they “recrerate” or mimic embroynic environment in limb buds development.

 

THE AVENGER

Indications

One-stage cartilage restoration with chondrocytes and MSC is the preferred technique for focal cartilage lesions on the femoral condyles or trochlear, ICRS II or III, > 1 cm², in adult patients with stable and well-aligned knees and meniscal loss < 50%22,25.

 

One-Stage Restoration with Chondrocytes and Bone Marrow-Derived Mesenchymal Stem Cells: Surgical Technique22,25

Surgery can be performed via arthroscopy or a mini-arthrotomy approach. Cartilage defects are

debrided with curettes, removing the calcified layer and creating vertical and stable margins (Figure 1).

Cartilage pieces and BM-MSC are harvested afterward (Figures 2 and 3). Autologous chondrons (after enzymatic digestion of the minced cartilage) and MSCs are combined in a 1:9 ratio (standard) or 2:8 ratio (high yield) (Figures 4 and 5), depending on the number of isolated chondrons17.

The lesion is measured, and a scaffold is prepared to meet the shape and thickness of the defect when implemented. In the next step the scaffold is implanted in the defect seeded with the cell mixture and further stabilized with the use of fibrin glue (Figures 6 and 7). Seeding after the fixation of the scaffold results in less cellular death resulting from manipulation36. The implantation of the cell mixture is also feasible directly in the fibrin glue without a scaffold.

Finally, the knee is tested for passive range of motion, checking the implant stability.

 

Outcomes: The Promise of a Definite Solution

One-stage cartilage restoration using chondrocytes and MSC has proved to be a safe and reproducible technique, improving clinical outcomes and tissue quality of its predecessor two-stage ACI at two-year follow-up17,25.

Similarly, de Windt et al17 implemented a combination of recycled chondrons from the lesion rim and cryopreserved allogeneic BM-MSC suspended in fibrin glue in 35 patients with full-thickness cartilage injuries with a mean size of 3.2 cm² ± 0.7, in a first-in-man clinical trial. Patient-reported clinical outcomes KOOS and VAS significantly improved from baseline scores up at 18 months after surgery, with the most considerable improvement at 3-month follow-up. Moreover, biochemical MRI, second-look arthroscopies, and histologic evaluation revealed a similar or higher quality in the new cartilage than in that obtained after ACI at 12 months. Hyaline-like cartilage was confirmed in almost 95% of the patients.

At a 5-year follow-up, the same patient cohort maintained the clinical benefits along with the follow-up, with fluctuations around the second year, probably related to the return to sporting activities. No serious adverse effects were recorded, and five patients required reintervention22.

Similarly, in a prospective multicenter study using a combination of primary chondrocytes and bone marrow mononucleated cells in a hyaluronan-based scaffold, Slynarski et al25 reported successful lesion filling in all 40 patients with ICRS II and III chondral lesions ≤ 2.6 cm² at 3-month follow up and in all patients that completed the 2-year follow-up (20% loss to follow-up). Significant improvement in KOOS and IKDC patient-reported outcomes were achieved throughout the study with confirmed hyaline-like cartilage in 22 of 40 patients post-operative biopsies.

Similar complications have been reported in one-stage procedures compared to those observed in ACI and microfractures25. Arthralgia, joint effusion, and reoperation were the most common among them22,25.

Future investigations should evaluate the differences in outcomes when higher cellularity is seeded in the chondral defect or differences in the chondrogenic potential of chondrocytes harvested from different local donor sites.

 

CONCLUSION

One-stage cartilage restoration using a combination of chondrocytes and BM-MSC is a safe and reproducible surgical procedure with satisfactory short- and mid-term clinical outcomes. Similar or better new synthesized cartilage should be expected in the defect compared to ACI with superior cost-effectiveness. Further research may consolidate one-stage cell-based cartilage restoration procedures as the standard of treatment for focal cartilage injuries.

 

 

Konrad Słynarski M.D., Ph.D.

Orthopedic Surgeon 

Słynarski Knee Clinic 

Warsaw, Poland

 

Theodorakys Marín Fermín M.D. 

Orthopedic Surgeon 

Hospital Universitario Periférico de Coch. 

Caracas, Venezuela

 

Emmanouil Papakostas M.D., F.E.B.S.M.

Orthopaedic Surgeon

Aspetar Orthopaedic and Sports Medicine Hospital

Doha, Qatar

 

Contact: konrad@slynarski.pl

 

 

 

References

  1. da Cunha Cavalcanti FM, Doca D, Cohen M, Ferretti M. Updating on diagnosis and treat-ment of chondral lesion of the knee. Rev Bras Ortop 2015;47:12–20.
  2. Curl W, Krome J, et al. Cartilage injuries: A review of 31,516 knee arthroscopies. Arthros-copy. 1997;13:456–460.
  3. Flanigan DC, Harris JD, Trinh TQ, Siston RA, Brophy RH. Prevalence of chondral defects in athletes' knees: a systematic review. Med Sci Sports Exerc 2010;42(10):1795e801.
  4. Totlis T, Marín Fermín T, Kalifis G, Terzidis I, Maffulli N, Papakostas E. Arthroscopic deb-ridement for focal articular cartilage lesions of the knee: A systematic review. Sur-geon. 2021 Jan 8:S1479-666X(20)30184-0.
  5. Carballo CB, Nakagawa Y, Sekiya I, Rodeo SA. Basic Science of Articular Cartilage. Clin Sports Med. 2017 Jul;36(3):413-425.
  6. Mow VC, Rosenwasser M. Articular cartilage: biomechanics. In: Woo SL-Y, Buckwalter JA, eds. Injury and repair to the musculoskeletal soft tissues. Park Ridge (IL): American Academy of Orthopaedic Surgeons; 1988. p. 427–46.
  7. Minas T, Glowacki J. Cartilage Repair and Regeneration. In: Minas T, ed. A Primer in Carti-lage Repair and Joint Preservation of the Knee. Philadelphia (PA): W.B. Saunders; 2011. p. 8-11.
  8. Redman SN, Oldfield SF, Archer CW. Current strategies for articular cartilage repair. Eur Cell Mater 2005;9:23–32.
  9. Morito T, Muneta T, Hara K, et al. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford) 2008;47:1137–43.
  10. Sekiya I, Ojima M, Suzuki S, et al. Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J Orthop Res 2012;30:943–9.
  11. Dzioba RB. The classification and treatment of acute articular cartilage lesions. Arthrosco-py. 1988;4:72–80.
  12. Nehrer S, Spector M, Minas T. Histologic analysis of tissue after failed cartilage repair pro-cedures. Clin Orthop Relat Res. 1999; (365):149–162.
  13. Minas T. Chondral Injury and Osteoarthritis: The Impact of Articular Cartilage Lesions. In: Minas T, ed. A Primer in Cartilage Repair and Joint Preservation of the Knee. Philadel-phia (PA): W.B. Saunders; 2011. p. 4-5.
  14. Campbell AB, Pineda M, Harris JD, Flanigan DC. Return to sport after articular cartilage re-pair in athletes’ knees: a systematic review. Arthroscopy. 2016;32(4):651-668, e651.
  15. Hanaoka C, Fausett C, Jayabalan P. Nonsurgical Management of Cartilage Defects of the Knee: Who, When, Why, and How? J Knee Surg. 2020 Nov;33(11):1078-1087.
  16. Kwon H, Brown WE, Lee CA, Wang D, Paschos N, Hu JC, Athanasiou KA. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat Rev Rheumatol. 2019 Sep;15(9):550-570.
  17. de Windt TS, Vonk LA, Slaper-Cortenbach ICM, Nizak R, van Rijen MHP, Saris DBF. Allogene-ic MSCs and Recycled Autologous Chondrons Mixed in a One-Stage Cartilage Cell Transplantion: A First-in-Man Trial in 35 Patients. Stem Cells. 2017 Aug;35(8):1984-1993.
  18. Everhart JS, Campbell AB, Abouljoud MM, Kirven JC, Flanigan DC. Cost-efficacy of Knee Cartilage Defect Treatments in the United States. Am J Sports Med. 2020 Jan;48(1):242-251.
  19. Kon E, Filardo G, Berruto M, Benazzo F, Zanon G, Della Villa S, Marcacci M. Articular carti-lage treatment in high-level male soccer players: a prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus micro-fracture. Am J Sports Med. 2011 Dec;39(12):2549-57.
  20. Mistry H, Connock M, Pink J, Shyangdan D, Clar C, Royle P, Court R, Biant LC, Metcalfe A, Waugh N. Autologous chondrocyte implantation in the knee: systematic review and economic evaluation. Health Technol Assess. 2017; 21(6):1–294.
  21. Gobbi A, Whyte GP. Long-term Clinical Outcomes of One-Stage Cartilage Repair in the Knee With Hyaluronic Acid-Based Scaffold Embedded With Mesenchymal Stem Cells Sourced From Bone Marrow Aspirate Concentrate. Am J Sports Med. 2019 Jun;47(7):1621-1628.
  22. Saris TFF, de Windt TS, Kester EC, Vonk LA, Custers RJH, Saris DBF. Five-Year Outcome of 1-Stage Cell-Based Cartilage Repair Using Recycled Autologous Chondrons and Allogenic Mesenchymal Stromal Cells: A First-in-Human Clinical Trial. Am J Sports Med. 2021 Mar;49(4):941-947.
  23. Moseley JB Jr, Anderson AF, Browne JE, Mandelbaum BR, Micheli LJ, Fu F, Erggelet C. Long-term durability of autologous chondrocyte implantation: a multicenter, observa-tional study in US patients. Am J Sports Med. 2010 Feb;38(2):238-46.
  24. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010 Jun;38(6):1117-24.
  25. Słynarski K, de Jong WC, Snow M, Hendriks JAA, Wilson CE, Verdonk P. Single-Stage Autol-ogous Chondrocyte-Based Treatment for the Repair of Knee Cartilage Lesions: Two-Year Follow-up of a Prospective Single-Arm Multicenter Study. Am J Sports Med. 2020 May;48(6):1327-1337.
  26. Anz AW, Hackel JG, Nilssen EC, Andrews JR. Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. J Am Acad Orthop Surg. 2014;22:68–79.
  27. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9:641–50.
  28. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013 Nov 15;45(11):e54.
  29. Deng Z, Jin J, Wang S, Qi F, Chen X, Liu C, Li Y, Ma Y, Lyu F, Zheng Q. Narrative review of the choices of stem cell sources and hydrogels for cartilage tissue engineering. Ann Transl Med. 2020 Dec;8(23):1598.
  30. Dominici M, le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keat-ing A, Prockop D, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cyto-therapy. 2006;8:315–7.
  31. Baghaban Eslaminejad M, Malakooty Poor E. Mesenchymal stem cells as a potent cell source for articular cartilage regeneration. World J Stem Cells. 2014 Jul 26;6(3):344-54.
  32. Hyer CF, Berlet GC, Bussewitz BW, Hankins T, Ziegler HL, Philbin TM. Quantitative assess-ment of the yield of osteoblastic connective tissue progenitors in bone marrow aspi-rate from the iliac crest, tibia, and calcaneus. J Bone Joint Surg Am. 2013;95:1312–6.
  33. Caplan AI. There Is No "Stem Cell Mess". Tissue Eng Part B Rev. 2019 Aug;25(4):291-293.
  34. Guimarães-Camboa N, Cattaneo P, Sun Y, Moore-Morris T, Gu Y, Dalton ND, Rockenstein E, Masliah E, Peterson KL, Stallcup WB, Chen J, Evans SM. Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo. Cell Stem Cell. 2017 Mar 2;20(3):345-359.e5.
  35. Caplan AI. What's in a name? Tissue Eng Part A. 2010 Aug;16(8):2415-7.
  36. Zhao Z, Zhou X, Guan J, Wu M, Zhou J. Co-implantation of bone marrow mesenchymal stem cells and chondrocytes increase the viability of chondrocytes in rat osteo-chondral defects. Oncol Lett. 2018 May;15(5):7021-7027.
  37. Zhao Z, Zhou X, Guan J, Wu M, Zhou J. Co-implantation of bone marrow mesenchymal stem cells and chondrocytes increase the viability of chondrocytes in rat osteo-chondral defects. Oncol Lett. 2018 May;15(5):7021-7027.
  38. Cooke ME, Allon AA, Cheng T, Kuo AC, Kim HT, Vail TP, Marcucio RS, Schneider RA, Lotz JC, Alliston T. Structured three-dimensional co-culture of mesenchymal stem cells with chondrocytes promotes chondrogenic differentiation without hypertrophy. Osteoar-thritis Cartilage. 2011 Oct;19(10):1210-8.
  39. Hendriks JAA, Miclea RL, Schotel R, de Bruijn E, Moroni L, Karperien M, Riesle J, van Blitterswijk CA. Primary chondrocytes enhance cartilage tissue formation upon co-culture with a range of cell types. Soft Matter. 2010;6:5080-5088.
  40. Hildner F, Concaro S, Peterbauer A, Wolbank S, Danzer M, Lindahl A, Gatenholm P, Redl H, van Griensven M. Human adipose-derived stem cells contribute to chondrogenesis in coculture with human articular chondrocytes. Tissue Eng Part A. 2009;15(12):3961-3969.
  41. de Windt TS, Hendriks JAA, Zhao X, et al. Concise review: unraveling stem cell cocultures in regenerative medicine. Which cell interactions steer cartilage regeneration and how? Stem Cells Transl Med. 2014;3(6):723-733.
  42. Biant LC, Simons M, Gillespie T, McNicholas MJ. Cell viability in arthroscopic versus open autologous chondrocyte implantation. Am J Sports Med. 2017;45(1):77-81.
  43. Hua Q, Knudson CB, Knudson W. Internalization of hyaluronan by chondrocytes occurs via receptor-mediated endocytosis. J Cell Sci. 1993;106:365-375.
  44. Knudson W, Ishizuka S, Terabe K, Askew EB, Knudson CB. The pericellular hyaluronan of ar-ticular chondrocytes. Matrix Biol. 2019 May;78-79:32-46.
  45. Zhao X, Hu DA, Wu D, He F, Wang H, Huang L, Shi D, Liu Q, Ni N, Pakvasa M, Zhang Y, Fu K, Qin KH, Li AJ, Hagag O, Wang EJ, Sabharwal M, Wagstaff W, Reid RR, Lee MJ, Wolf JM, El Dafrawy M, Hynes K, Strelzow J, Ho SH, He TC, Athiviraham A. Applications of Bio-compatible Scaffold Materials in Stem Cell-Based Cartilage Tissue Engineering. Front Bioeng Biotechnol. 2021 Mar 25;9:603444.
  46. Calvo R, Figueroa D, Figueroa F, Bravo J, Contreras M, Zilleruelo N. Treatment of Patello-femoral Chondral Lesions Using Microfractures Associated with a Chitosan Scaffold: Mid-Term Clinical and Radiological Results. Cartilage. 2021 Apr 27:19476035211011506.
  47. Solchaga LA, Dennis JE, Goldberg VM, Caplan AI. Hyaluronic acid-based polymers as cell carriers for tissue-engineered repair of bone and cartilage. J Orthop Res. 1999 Mar;17(2):205-13.

 

 

 

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