**7.4.9 Role of weight-bearing**

Our biopsy specimens from cases with subchondral drilling followed by postoperative intraarticular injections of PBPC in combination with HA showed histologic features of hyaline cartilage with anti–collagen type I stain (used to highlight collagen type I), anti– collagen type II stain (used to highlight collagen type II), and Safranin-O stain (used to highlight proteoglycans), with the exception of one histologic sample showing mixed cartilage. This biopsy specimen was from an area of abrasion notchplasty, which represented a non–weight-bearing region. Comparison of biopsy specimens from this non– weight-bearing area to those from a weight-bearing area in the same patient has led us to theorize that early partial-weight-bearing is essential for the regeneration and alignment of collagen type II (Fig 18).

#### **7.4.10 Articular cartilage imaging of the knee**

Articular cartilage is visible on most standard MRI sequences as a band of intermediate to high signal covering the articular aspect of the bone. Non-injured articular cartilage normally shows a continuous subchondral dark line (low-signal) below the articular cartilage. This dark line likely represents the layer of calcified cartilage and the associated subchondral bone plate. It may be accentuated by chemical shift artifact (of water and fat molecules in the same voxel canceling their respective signals thereby resulting in signal loss). Fig 41 illustrates the articular cartilage and subchondral bone on a sagittal PD image. Evaluating postoperative MRIs, we assessed the restoration of the dark line as evidence of calcified cartilage with subchondral bone healing and fill of the defect as indicative of cartilage regeneration.

Our current imaging preference for assessing chondral lesions of the knee joint utilize 2D PD and PDFS sequences using a high field (1.5T) extremity MRI (GE Medical Systems) – Fig 42. This has the benefits of improved signal to noise and higher resolution. Fig 43 showing examples of chondral lesions seen following MRI scan with arthroscopic correlation (Fig 44). Our earlier cartilage images were obtained by an open MRI system operating at 0.35T (Magnetom C!, Siemens Medical Solutions, Erlangen, Germany) using an extremity receive coil.

MRI scans were utilized preoperatively as part of the diagnostic work up and postoperatively to monitor healing of the chondral defects. We performed MRI scans at

**7.4.8 The importance of PBPC + HA as adjuvant therapy following ideal subchondral** 

Case 6 emphasizes on the importance of the improved technique of ideal drilling in an uncontained lesion. Cases 7 & 8 illustrates the importance of postoperative intraarticular

Possible reasons as to why the microfracture technique has not been successful in achieving consistent coverage with hyaline cartilage can be explained by what is seen on second-look arthroscopy in cases 6, 7 and 8. Firstly, microfractures are usually placed 3 to 5 mm apart and do not penetrate much deeper than the calcified cartilage layer. Microfractures placed more superficially and further apart as compared to ideal subchondral drilling explains one of the possible reasons why the microfracture technique is inconsistent in producing satisfactory articular cartilage repair. Secondly, like the animal model in Fig 9, without postoperative adjunct therapy with PBPC + HA, the regenerated tissue will always be of inferior quality.

Our biopsy specimens from cases with subchondral drilling followed by postoperative intraarticular injections of PBPC in combination with HA showed histologic features of hyaline cartilage with anti–collagen type I stain (used to highlight collagen type I), anti– collagen type II stain (used to highlight collagen type II), and Safranin-O stain (used to highlight proteoglycans), with the exception of one histologic sample showing mixed cartilage. This biopsy specimen was from an area of abrasion notchplasty, which represented a non–weight-bearing region. Comparison of biopsy specimens from this non– weight-bearing area to those from a weight-bearing area in the same patient has led us to theorize that early partial-weight-bearing is essential for the regeneration and alignment of

Articular cartilage is visible on most standard MRI sequences as a band of intermediate to high signal covering the articular aspect of the bone. Non-injured articular cartilage normally shows a continuous subchondral dark line (low-signal) below the articular cartilage. This dark line likely represents the layer of calcified cartilage and the associated subchondral bone plate. It may be accentuated by chemical shift artifact (of water and fat molecules in the same voxel canceling their respective signals thereby resulting in signal loss). Fig 41 illustrates the articular cartilage and subchondral bone on a sagittal PD image. Evaluating postoperative MRIs, we assessed the restoration of the dark line as evidence of calcified cartilage with subchondral bone healing and fill of the defect as indicative of

Our current imaging preference for assessing chondral lesions of the knee joint utilize 2D PD and PDFS sequences using a high field (1.5T) extremity MRI (GE Medical Systems) – Fig 42. This has the benefits of improved signal to noise and higher resolution. Fig 43 showing examples of chondral lesions seen following MRI scan with arthroscopic correlation (Fig 44). Our earlier cartilage images were obtained by an open MRI system operating at 0.35T (Magnetom C!, Siemens Medical Solutions, Erlangen, Germany) using an extremity receive

MRI scans were utilized preoperatively as part of the diagnostic work up and postoperatively to monitor healing of the chondral defects. We performed MRI scans at

**drilling** 

injections of PBPC + HA.

**7.4.9 Role of weight-bearing** 

collagen type II (Fig 18).

cartilage regeneration.

coil.

**7.4.10 Articular cartilage imaging of the knee** 

shorter intervals for our first 10 patients. Scans were performed on the first postoperative day as a baseline to document the chondral defect after debridement and subchondral drilling. Serial studies were then collected in the postoperative period (at 6, 12, 18, 24 months and beyond) to evaluate the filling of the defect by regenerated cartilage and changes in the subchondral bone.

Fig. 41. Articular cartilage as depicted by sagittal PD image at the tibial plateau. Black arrow showing the surface of the tibial plateau articular cartilage and red arrow showing the "Black line" that separates the articular cartilage from the subchondral bone. This layer correlates with the tidemark / calcified cartilage / subchondral bone plate layers.

Fig. 42. A patient with her right knee in a high field extremity (1.5T) MRI (GE Medical Systems).

Articular Cartilage Regeneration with Stem Cells 169

MRI scans performed on the first postoperative day showed the chondral defects as well delineated from surrounding healthy cartilage. The chondral defects were bare or partially filled in with blood clot. Drill tracts and subchondral marrow edema were clearly observed (Figures 45 to 47). Subchondral bone is disrupted, i.e. there is loss of the continuity of the subchondral black line. Over the course of two years, filling-in of the chondral defects by material of similar or same signal as articular cartilage was observed. Re-establishment of subchondral black line paralleled the progressive resolution of

Serial MRI scans of our first patient undergoing this treatment are presented in Figure 45. After full debridement and drilling, the chondral defect is well visualized as a bare area partially filled by clot (Figure 45A). The low signal subchondral bone is disrupted and low signal drill tracts are visualized within the subchondral marrow edema. The disruption of the subchondral dark line represents a conduit through the calcified cartilage layer. Serial scans showed progressive filling of chondral defects by material of similar appearance as articular cartilage, resolution of marrow edema and reappearance of the continuous subchondral dark line (Figure 45B). At one to two years, the calcified cartilage, as depicted by the low signal band, becomes almost as thick at the site of drilling as in the surrounding

healthy areas. (Figure 45D). Figures 46 and 47 present an additional patient.

Fig. 45. Serial MRI evaluation (STIR images at 0.35T). Postoperative (Post-op): note the disruption of the subchondral dark line (red arrow). (B) 2 months: partial resolution of marrow edema and reappearance of the continuous subchondral dark line (red arrow). (C) 10 months: almost complete resolution of marrow edema and filling of defect. (D) 20 months: complete healing of defect and re-establishment of subchondral dark line

representing healing of the calcified cartilage layer.

marrow edema.

Fig. 43. Images of chondral lesions demonstrated by extremity high field MRI at 1.5T. (A) Chondral flap tear of the medial femoral condyle (white arrow) with red arrow showing a delaminated chondral lesion over the lateral femoral condyle (PDFS). (B) The corresponding chondral lesion of the lateral femoral condyle (red arrow) on a sagittal PD image.

Fig. 44. Corresponding arthroscopic view of the lesions from the medial femoral condyle (MFC) and lateral femoral condyle (LFC) as in Fig 43.

Fig. 43. Images of chondral lesions demonstrated by extremity high field MRI at 1.5T. (A) Chondral flap tear of the medial femoral condyle (white arrow) with red arrow showing a delaminated chondral lesion over the lateral femoral condyle (PDFS). (B) The corresponding

Fig. 44. Corresponding arthroscopic view of the lesions from the medial femoral condyle

(MFC) and lateral femoral condyle (LFC) as in Fig 43.

chondral lesion of the lateral femoral condyle (red arrow) on a sagittal PD image.

MRI scans performed on the first postoperative day showed the chondral defects as well delineated from surrounding healthy cartilage. The chondral defects were bare or partially filled in with blood clot. Drill tracts and subchondral marrow edema were clearly observed (Figures 45 to 47). Subchondral bone is disrupted, i.e. there is loss of the continuity of the subchondral black line. Over the course of two years, filling-in of the chondral defects by material of similar or same signal as articular cartilage was observed. Re-establishment of subchondral black line paralleled the progressive resolution of marrow edema.

Serial MRI scans of our first patient undergoing this treatment are presented in Figure 45. After full debridement and drilling, the chondral defect is well visualized as a bare area partially filled by clot (Figure 45A). The low signal subchondral bone is disrupted and low signal drill tracts are visualized within the subchondral marrow edema. The disruption of the subchondral dark line represents a conduit through the calcified cartilage layer. Serial scans showed progressive filling of chondral defects by material of similar appearance as articular cartilage, resolution of marrow edema and reappearance of the continuous subchondral dark line (Figure 45B). At one to two years, the calcified cartilage, as depicted by the low signal band, becomes almost as thick at the site of drilling as in the surrounding healthy areas. (Figure 45D). Figures 46 and 47 present an additional patient.

Fig. 45. Serial MRI evaluation (STIR images at 0.35T). Postoperative (Post-op): note the disruption of the subchondral dark line (red arrow). (B) 2 months: partial resolution of marrow edema and reappearance of the continuous subchondral dark line (red arrow). (C) 10 months: almost complete resolution of marrow edema and filling of defect. (D) 20 months: complete healing of defect and re-establishment of subchondral dark line representing healing of the calcified cartilage layer.

Articular Cartilage Regeneration with Stem Cells 171

Fig. 47. Sagittal PD MRI (0.35T) of patient in Figure 46. (A) Postoperative (Post-op) MRI: chondral lesions at the lateral patella and lateral femoral chondyle (arrows). Note the disruption to the continous low signal calcified cartilage layer at both sites. (B) MRI at one year after surgery showing the re-establishment of the subchondral calcified cartilage layer

The re-establishment of the calcified cartilage layer and healing of the subchondral bone are important MRI features of articular cartilage regeneration in our series. This is accompanied by filling of the chondral defect. Following arthroscopic subchondral drilling, MRI images revealed extensive marrow edema and interruption of the calcified cartilage layer together with the underlying subchondral bone. This is shown as disruption of the low signal subchondral dark line. As the injected PBPC seed the blood clot scaffold in the presence of HA, chondrogenesis is initiated with the formation of chondrocytes which then occupy the drill holes. This process is gradually replaced by bone resulting in subchondral bone repair. Gradual resolution of marrow edema is observed. The subchondral dark line progressively re-appears on MRI scans indicating the re-establishment of the calcified cartilage layer and healing of the subchondral bone (Figures 45 to 47). This evidence is provided from the histology shown on Figures 20 and 21. Depending on whether the lesion is a contained or uncontained lesion, chondrogenesis follows the gradual re-appearance of this subchondral

Since starting clinical trials in 2007, 223 cartilage regeneration cases have been performed on 205 patients. Cases were varied including 38 cases involving isolated cartilage lesions, 92 cases involving multiple cartilage lesions, 54 cases involving patellofemoral cartilage lesions, 7 cases involving concomitant lower limb realignment procedures, and 32 cases involving ligament reconstruction. When evaluating two-year clinical outcomes, 24 months has passed for 155 of these 223 cases. Within this group, 52 cases have preoperative, 12-month, and 24-month IKDC values available for clinical outcome evaluation. This group had a preoperative IKDC average of 50.5, a 12-month IKDC

(long arrows) together with articular cartilage regeneration (short arrows).

dark line on serial MRI scans (Figures 24 and 26).

**7.4.11 Phase I study clinical outcomes** 

Fig. 46. A 40-year-old woman with patellar dislocation (STIR images at 0.35T). (A) Preoperative MRI with evidence of a delaminating articular cartilage injury and medial patellar femoral ligament (MPFL) injury. The injury was treated with arthroscopic lateral release, subchondral drilling and repair of the MPFL. (B) Postoperative (Post-op) MRI following arthroscopic lateral patellar release (red arrow) and subchondral drilling showing interruption of the low signal subchondral calcified cartilage (white arrows). (C) At one year following surgery, MRI revealed a healed lateral retinaculum (red arrow), re-establishment of the subchondral calcified cartilage (white arrows) and evidence of articular cartilage regeneration at the lateral patella facet.

Fig. 46. A 40-year-old woman with patellar dislocation (STIR images at 0.35T). (A) Preoperative MRI with evidence of a delaminating articular cartilage injury and medial patellar femoral ligament (MPFL) injury. The injury was treated with arthroscopic lateral release, subchondral drilling and repair of the MPFL. (B) Postoperative (Post-op) MRI following arthroscopic lateral patellar release (red arrow) and subchondral drilling showing interruption of the low signal subchondral calcified cartilage (white arrows). (C) At one year following surgery, MRI revealed a healed lateral retinaculum (red arrow), re-establishment of the subchondral calcified cartilage (white arrows) and evidence of articular cartilage

regeneration at the lateral patella facet.

Fig. 47. Sagittal PD MRI (0.35T) of patient in Figure 46. (A) Postoperative (Post-op) MRI: chondral lesions at the lateral patella and lateral femoral chondyle (arrows). Note the disruption to the continous low signal calcified cartilage layer at both sites. (B) MRI at one year after surgery showing the re-establishment of the subchondral calcified cartilage layer (long arrows) together with articular cartilage regeneration (short arrows).

The re-establishment of the calcified cartilage layer and healing of the subchondral bone are important MRI features of articular cartilage regeneration in our series. This is accompanied by filling of the chondral defect. Following arthroscopic subchondral drilling, MRI images revealed extensive marrow edema and interruption of the calcified cartilage layer together with the underlying subchondral bone. This is shown as disruption of the low signal subchondral dark line. As the injected PBPC seed the blood clot scaffold in the presence of HA, chondrogenesis is initiated with the formation of chondrocytes which then occupy the drill holes. This process is gradually replaced by bone resulting in subchondral bone repair. Gradual resolution of marrow edema is observed. The subchondral dark line progressively re-appears on MRI scans indicating the re-establishment of the calcified cartilage layer and healing of the subchondral bone (Figures 45 to 47). This evidence is provided from the histology shown on Figures 20 and 21. Depending on whether the lesion is a contained or uncontained lesion, chondrogenesis follows the gradual re-appearance of this subchondral dark line on serial MRI scans (Figures 24 and 26).

#### **7.4.11 Phase I study clinical outcomes**

Since starting clinical trials in 2007, 223 cartilage regeneration cases have been performed on 205 patients. Cases were varied including 38 cases involving isolated cartilage lesions, 92 cases involving multiple cartilage lesions, 54 cases involving patellofemoral cartilage lesions, 7 cases involving concomitant lower limb realignment procedures, and 32 cases involving ligament reconstruction. When evaluating two-year clinical outcomes, 24 months has passed for 155 of these 223 cases. Within this group, 52 cases have preoperative, 12-month, and 24-month IKDC values available for clinical outcome evaluation. This group had a preoperative IKDC average of 50.5, a 12-month IKDC

Articular Cartilage Regeneration with Stem Cells 173

above baseline and remained stable in the refined method at 25 points above baseline (Zeifang et al, 2010). This compares to our rise above a baseline IKDC of 50.5 by 20 points at 12 months, 20 points at 24 months, and 21 points at 30 months (Fig 48). Of note, our patient group has a mean age of 47.1 years and included patients with multiple chondral lesions,

Our clinical results indicate that the regenerated tissue is resilient and coincide with histological results suggesting that this technique produces hyaline cartilage. However, evaluating phase I data has weaknesses. As this portion of the clinical trial has included evolution in technique and cell processing, there is some inherent variation. Additionally, IKDC collection was inconsistent in the initial phases. Also, when attempting to evaluate this early data, there is no control group available for comparison. Currently a randomized

Specific complications are mild bone pain associated with Neupogen injections, and discomfort of PBSC harvesting and localized pain following intraarticular injections with PBPC and HA. One male patient in his mid-forties had a previous infection from Anterior Cruciate Ligament (ACL) surgery, multiple microfractures and subsequent ACL revision surgery with postoperative PBPC and HA. He had recurrence of intercondylar osteophytes and reactive arthritis and eventually chose a total knee replacement. Three other patients had secondary procedure for persistent osteophytes and treatment for further areas of

It is evident that with adjuvant PBPC and HA therapy, chondrogenesis is possible with hyaline cartilage, but a small proportion of patients may return for further treatment

A randomized controlled trial comparing a group with PBPC and HA injections with a group with HA injection alone following arthroscopic subchondral drilling is currently under way, being supervised by the first author. The early results seem to support the benefit of adjuvant postoperative intraarticular injections of PBPC in combination with

Our theory is that providing a high percentage of immature multipotent progenitor cells into the right environment allows these cells to populate areas of subchondral drilling and regenerate hyaline cartilage. Our histologic findings of chondrocytes below the calcified cartilage layer at a subchondral drill hole (Figs 20 and 21) and the porcine model (Lee et al, 2007) illustrating mesenchymal stem cells at the base of newly formed cartilage support the idea that injected progenitor cells are attracted to the site of marrow injury, proliferate into chondrocytes, and regenerate hyaline cartilage from the subchondral base. We theorize that the addition of matrix substance, in the form of HA and passive stimulating kinetic movement of the involved joint (continuous passive motion), provides chemical and cellular signals for regeneration. Partial to full weight-bearing in the early phase of rehabilitation provides the essential environment to assist in the remodelling of the collagen fibrils to align

because of newly diagnosed areas of chondral degeneration in the treated knee.

while Zeifang et al. (2010) evaluated isolated defects of the femoral condyle.

controlled trial is underway under the direction of the first author.

**7.4.12 Complications** 

chondral degeneration.

**7.6 Summary of theory** 

HA.

**7.5 Current control randomized trial** 

along the axis of weight transmission.

average of 70, and a 24-month IKDC average of 70. 30 patients had 30-month data available and illustrated a 30-month IKDC average of 71 (Fig 48).

Fig. 48. International Knee Documentation Committee (IKDC) outcomes.

Our IKDC results illustrated a significant increase similar to studies documenting overall outcomes in the literature with marrow stimulation and chondrocyte implantation. Historically, microfracture has shown a peak functional outcome at 24 months (Blevins et al, 1998; Peterson et al, 2000; Steadman et al, 2003; Gobbi et al, 2005, Mithoefer et al, 2005; Knutsen et al, 2007). Two studies have illustrated a decline after the first 18 to 24 months with microfracture, including Mithoefer et al (2005) documenting 69% of their patients reporting lower IKDC scores after 24 months. Conversely, two outcome studies have found sustained improvement at the 24-month time interval (Steadman et al, 2003; Kneutsen et al, 2004). In comparison of these four studies, the average age of the study groups documenting decline was 39.5 years and 41 years. In contrast, the average age of the studies documenting sustained improvement was 30.4 years and 31.1 years (Steadman et al, 2003; Mithoefer et al, 2005; Kruez et al, 2006; Knutsen et al, 2004). In a group with an average age of 47.1 years, our IKDC scores showed sustained improvement at 24 months with 30 cases documenting continued improvement at 30 months.

Comparing microfracture and chondrocyte implantation, decisive superiority has not been established. Two randomized studies have sought to directly compare outcomes with differing results. Saris et al. (2009) found significantly better outcomes with ACI at 36 months. They found a continued increase in Knee Injury and Osteoarthritis Outcome Scores (KOOS) from 6 to 36 months with ACI and a plateau in scores at 18 months with microfracture (Saris et al, 2009). However, Knutsen et al. found no significant clinical or radiographic difference between microfracture and ACI at 60 months utilizing four clinical outcome scoring systems and 2 radiologic outcome systems (Knutsen et al,2007). Zeifang et al. (2010) in comparison of conventional methods of ACI with refined methods of ACI for treatment of femoral chondral lesions found an increase from a baseline IKDC (51.1) by 21 points and 25 points respectively. This series had an average age of 29.3 years (Zeifang et al, 2010). At 24 months, this rise declined slightly in the conventional method to 19 points above baseline and remained stable in the refined method at 25 points above baseline (Zeifang et al, 2010). This compares to our rise above a baseline IKDC of 50.5 by 20 points at 12 months, 20 points at 24 months, and 21 points at 30 months (Fig 48). Of note, our patient group has a mean age of 47.1 years and included patients with multiple chondral lesions, while Zeifang et al. (2010) evaluated isolated defects of the femoral condyle.

Our clinical results indicate that the regenerated tissue is resilient and coincide with histological results suggesting that this technique produces hyaline cartilage. However, evaluating phase I data has weaknesses. As this portion of the clinical trial has included evolution in technique and cell processing, there is some inherent variation. Additionally, IKDC collection was inconsistent in the initial phases. Also, when attempting to evaluate this early data, there is no control group available for comparison. Currently a randomized controlled trial is underway under the direction of the first author.

#### **7.4.12 Complications**

172 Modern Arthroscopy

average of 70, and a 24-month IKDC average of 70. 30 patients had 30-month data

**Pre Op 12 24 30 Months**

Our IKDC results illustrated a significant increase similar to studies documenting overall outcomes in the literature with marrow stimulation and chondrocyte implantation. Historically, microfracture has shown a peak functional outcome at 24 months (Blevins et al, 1998; Peterson et al, 2000; Steadman et al, 2003; Gobbi et al, 2005, Mithoefer et al, 2005; Knutsen et al, 2007). Two studies have illustrated a decline after the first 18 to 24 months with microfracture, including Mithoefer et al (2005) documenting 69% of their patients reporting lower IKDC scores after 24 months. Conversely, two outcome studies have found sustained improvement at the 24-month time interval (Steadman et al, 2003; Kneutsen et al, 2004). In comparison of these four studies, the average age of the study groups documenting decline was 39.5 years and 41 years. In contrast, the average age of the studies documenting sustained improvement was 30.4 years and 31.1 years (Steadman et al, 2003; Mithoefer et al, 2005; Kruez et al, 2006; Knutsen et al, 2004). In a group with an average age of 47.1 years, our IKDC scores showed sustained improvement at 24 months with 30 cases documenting

Comparing microfracture and chondrocyte implantation, decisive superiority has not been established. Two randomized studies have sought to directly compare outcomes with differing results. Saris et al. (2009) found significantly better outcomes with ACI at 36 months. They found a continued increase in Knee Injury and Osteoarthritis Outcome Scores (KOOS) from 6 to 36 months with ACI and a plateau in scores at 18 months with microfracture (Saris et al, 2009). However, Knutsen et al. found no significant clinical or radiographic difference between microfracture and ACI at 60 months utilizing four clinical outcome scoring systems and 2 radiologic outcome systems (Knutsen et al,2007). Zeifang et al. (2010) in comparison of conventional methods of ACI with refined methods of ACI for treatment of femoral chondral lesions found an increase from a baseline IKDC (51.1) by 21 points and 25 points respectively. This series had an average age of 29.3 years (Zeifang et al, 2010). At 24 months, this rise declined slightly in the conventional method to 19 points

available and illustrated a 30-month IKDC average of 71 (Fig 48).

Fig. 48. International Knee Documentation Committee (IKDC) outcomes.

continued improvement at 30 months.

**Increase in IKDC**

Specific complications are mild bone pain associated with Neupogen injections, and discomfort of PBSC harvesting and localized pain following intraarticular injections with PBPC and HA. One male patient in his mid-forties had a previous infection from Anterior Cruciate Ligament (ACL) surgery, multiple microfractures and subsequent ACL revision surgery with postoperative PBPC and HA. He had recurrence of intercondylar osteophytes and reactive arthritis and eventually chose a total knee replacement. Three other patients had secondary procedure for persistent osteophytes and treatment for further areas of chondral degeneration.

It is evident that with adjuvant PBPC and HA therapy, chondrogenesis is possible with hyaline cartilage, but a small proportion of patients may return for further treatment because of newly diagnosed areas of chondral degeneration in the treated knee.

#### **7.5 Current control randomized trial**

A randomized controlled trial comparing a group with PBPC and HA injections with a group with HA injection alone following arthroscopic subchondral drilling is currently under way, being supervised by the first author. The early results seem to support the benefit of adjuvant postoperative intraarticular injections of PBPC in combination with HA.

#### **7.6 Summary of theory**

Our theory is that providing a high percentage of immature multipotent progenitor cells into the right environment allows these cells to populate areas of subchondral drilling and regenerate hyaline cartilage. Our histologic findings of chondrocytes below the calcified cartilage layer at a subchondral drill hole (Figs 20 and 21) and the porcine model (Lee et al, 2007) illustrating mesenchymal stem cells at the base of newly formed cartilage support the idea that injected progenitor cells are attracted to the site of marrow injury, proliferate into chondrocytes, and regenerate hyaline cartilage from the subchondral base. We theorize that the addition of matrix substance, in the form of HA and passive stimulating kinetic movement of the involved joint (continuous passive motion), provides chemical and cellular signals for regeneration. Partial to full weight-bearing in the early phase of rehabilitation provides the essential environment to assist in the remodelling of the collagen fibrils to align along the axis of weight transmission.

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