Using a 3D Printer to Make a Knee Meniscus

Meniscus cartilage is the cushioning tissue between the femur and tibia bones of the knee.  Millions of Americans each year tear this cartilage.  Loss of the meniscus tissue can lead to arthritis.

In this novel approach, researchers in New York are using a 3D Printer to create a new meniscus.  They have studied in sheep so far with success.  In the future, it may be possible to use an MRI scan with a meniscus tear to help program a 3D printer to make you a new meniscus.  Treatment in human patients is not yet available but this is quite an intriguing possibility for the future.

Reference
TISSUE ENGINEERING

Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep

1. Chang H. Lee1, 
2. Scott A. Rodeo2, 
3. Lisa Ann Fortier3, 
4. Chuanyong Lu1, 
5. Cevat Erisken1 and 
6. Jeremy J. Mao1,*

Read More

Read the scientific abstract

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Microfracture Surgery Jadaveon Clowney

The Houston Texans' Jadeveon Clowney recently underwent "microfracture" surgery on his ailing right knee.  (See ESPN report)

The report suggests the talented Mr. Clowney will be out for 9 months or more.  Just what is microfracture surgery and why does it take as long to recovery as it does for a baby to born?

Microfracture Surgery

Let's start with the basics.  There are two types of cartilage in the knee.  The surface cartilage which covers the bone.  This is known as articular cartilage and can be thought of a type of cap or covering of the end of the bone.  This cartilage is present in any joint.  In the knee, there is another type of cartilage, the meniscus cartilage.  There are two menisci in the knee--medial (inside) and lateral (outside).  When the surface "articular" cartilage is damaged, the knee can become quite painful especially with loading and twisting.  Think rushing a passer for example.  Similar symptoms can occur when the meniscus is torn.  It is often difficult to distinguish between the two in terms of which one is the pain generator.

Microfracture surgery is an attempt to create a tire patch over a cartilage defect by poking a hole in the end of the bone and creating an access channel to the bone marrow.  The bone marrow then leaks out via the holes that are created and forms a clot which over time can help cover the defect.  It takes time, many months, for this surgery to work because the "patch" needs to mature.  This technique is useful for small defects in the cartilage but hasn't proven to be great for larger defects.  We do not know the size of Mr. Clowney's knee cartilage injury.

Recent evidence suggests that the addition of platelet-rich plasma can enhance microfracture surgery results.  This has been shown in basic science, preclinical and now clinical studies.

This type of surgery at such a young age is clearly not a good sign.  In the long run, he may require further intervention.  Please read the post below for further information about why we need to accelerate our regenerative medicine efforts.  Mr. Clowney is one of tens of millions of people worldwide with symptomatic cartilage damage.  We need to maximize outcomes of today's surgical techniques and develop new procedures to help keep our athletes and patients in the game.

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Fat Stem Cells help Knee Arthritis

Knee Arthritis is a very difficult problem to solve.  Millions of patients suffer daily from this progressive disease state.  A variety of novel biologic therapies are in development.

Stem cells can come from a variety of sources including your own fat.  These cells are known as adipose derived stem cells.  A recent study from Korea suggests there is value using this type of cell for knee arthritis.  Researchers gave patients escalating dose of the cells and found the high dose resulted in improved pain and function scores.  They also found the cartilage defect defect size decreased while the volume of cartilage in the knee increased.

Fat Derived Stem Cells

This data is encouraging and will need to be repeated prior to broad clinical use.  (See abstract below)

For patients with this problem, the horizon is bright with many potential options like stem cells from your own fat.

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Stem Cells. 2014 May;32(5):1254-66. doi: 10.1002/stem.1634.

Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial.

Jo CH1, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS.

Author information

Abstract

Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 10(7)cells), mid-dose (5.0 × 10(7)), and high-dose (1.0 × 10(8)) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 10(8) AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage.

Can Stem Cells Cure Knee Arthritis?

Can Stem Cells Cure Knee Arthritis?

Unfortunately, the answer to that question is not known today.  It is clear, however, that many novel regenerative therapies are emerging to help the tens of millions of patients worldwide that are suffering from knee arthritis.

First, we must explore what type of stem cells could be helpful in the treatment of arthritis.  Stem cells of various types can be obtained from your blood (peripheral derived stem cells), bone marrow (mesenchymal stem cells), fat (adipose derived stem cells), and even from umbilical cord blood.  Studies today are exploring various ways to extract, purify and concentrate many types of stem cells.  The cells can then be injected as a suspension into your knee, used as part of surgical procedure or even injected after an operation.

Microfracture of Damaged Knee Cartilage

One recent study (Vangsness et al 2014) showed how an injection of mesenchymal stem cells could lead to more meniscus tissue after a knee arthroscopy.  24% of the treated group were found to have at least 15% increased meniscal volume.  This is a small amount in only a a quarter of the patients but it does represent a start.  Another study published last year (Saw et al 2013), injected peripheral derived stem cells after a microfracture procedure and noted improvement in the cartilage quality.  Other approaches (Pak et al 2014) use adipose derived stem cells from liposuction in combination with platelet-rich plasma to treat meniscus tears.  Finally, a review (Anderson et al 2013) of potential stem cell therapies for knee cartilage outlines many potential and emerging options.

Also, a variety of procedures also use non-stem cells to treat arthritis of the knee.  One of the oldest is called autologous chondrocyte implantation.  This is where a biopsy of your own cartilage is taken and then grown in a lab.  The expanded cells and then reimplanted into an arthritic lesion of the knee.  Another procedure simply penetrates the bone under the defective cartilage.  This leads to leakage of some of the bone marrow along with your own the stem cells within the marrow into the defect.  This is called microfracture.  Yet another procedure uses juvenile cartilage that is minced and then glued into a arthritic zone of the knee.

It is clear that there are many competing approaches to the use of cells and stem cells to treat knee arthritis.  None have "cured" the problem.   There is, however, an earnest worldwide research effort that will produce clinically meaningful options for clinicians and patients.

Millions worldwide are waiting for that day.

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References
Anderson et al 2013
Saw et al 2013
Vangsness et al 2014
Pak et al 2014

Meta-analysis of Viscosupplementation for Knee Osteoarthritis Reveals Little Benefit

In the study outlined below, treatment with viscosupplementation (typically various forms of hyaluronic acid) was studied in over 12,500 patients.  This is an injection therapy used in patients with knee osteoarthritis.  It is usually reserved for patients that fail other forms of treatment.  Here is the conclusion of this study of studies:  "In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events."

Clearly, the data shows this treatment does not provide transformative value.  We need better options for patients with mild to moderate knee osteoarthritis.  Biologic therapies such as platelet rich plasma and autologous stem cells are evolving but still need significantly better studies to be used for knee osteoarthritis widely.  

It is often NOT discussed but patients with knee osteoarthritis can often benefit from weight reduction and leg strengthening via an exercise bike program.  Perhaps we should focus on these patient driven solutions first.

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Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review and Meta-analysis 

Anne W.S. Rutjes, PhD; Peter Jüni, MD; Bruno R. da Costa, MSc; Sven Trelle, MD; Eveline Nüesch, PhD; and Stephan Reichenbach, MD, MScBackground: Viscosupplementation, the intra-articular injection of hyaluronic acid, is widely used for symptomatic knee osteoarthritis.

Purpose: To assess the benefits and risks of viscosupplementation for adults with symptomatic knee osteoarthritis.

Data Sources: MEDLINE (1966 to January 2012), EMBASE (1980 to January 2012), the Cochrane Central Register of Controlled Trials (1970 to January 2012), and other sources.

Study Selection: Randomized trials in any language that compared viscosupplementation with sham or nonintervention control in adults with knee osteoarthritis.

Data Extraction: Primary outcomes were pain intensity and flare-ups. Secondary outcomes included function and serious adverse events. Reviewers used duplicate abstractions, assessed study quality, pooled data using a random-effects model, examined funnel plots, and explored heterogeneity using meta-regression.

Data Synthesis: Eighty-nine trials involving 12 667 adults met inclusion criteria. Sixty-eight had a sham control, 40 had a follow-up duration greater than 3 months, and 22 used cross-linked forms of hyaluronic acid. Overall, 71 trials (9617 patients) showed that viscosupplementation moderately reduced pain (effect size, −0.37 [95% CI, −0.46 to −0.28]). There was important between-trial heterogeneity and an asymmetrical funnel plot: Trial size, blinded outcome assessment, and publication status were associated with effect size. Five unpublished trials (1149 patients) showed an effect size of −0.03 (CI, −0.14 to 0.09). Eighteen large trials with blinded outcome assessment (5094 patients) showed a clinically irrelevant effect size of −0.11 (CI, −0.18 to −0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]).

Limitations: Trial quality was generally low. Safety data were often not reported.

Conclusion: In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events.

Link to Abstract

Unactivated Platelet Rich Plasma Proves Better

In a recently published study by Han et al published in the Journal of Bone and Joint Surgery (JBJS June 2009, American Volume), unactivated platelet rich plasma "stimulated chondrogenesis on Day 14 and osteogenesis on Days 28 and 56, whereas thrombin-activated platelet-rich plasma acted as an inhibitor of such events. In addition, inflammatory cells were detected in demineralized bone matrix samples that were mixed with thrombin-activated platelet-rich plasma. These cells were not present in matrix mixed with platelet-rich plasma alone." (See Full Abstract)

This data clearly supports the use of PRP that has NOT been activated by thrombin and/or calcium. This unactivated form of PRP has also proved useful for chronic tennis elbow. See References

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Platelet Rich Plasma and Cartilage Restoration

Platelet rich plasma was debated in a scientific session at the International Cartilage Research Society Meeting in Miami Florida this week. Dr. Allan Mishra, Dr. Vannini, Dr. Randelli and Dr. Johnson all spoke about PRP. It was moderated by Dr. Alberto Gobbi.

The discussion after these presentations centered around what type of PRP to use for what indications. It is clear that we need better data. The best published clinical data for tendon related injuries and disorders right now supports the use of PRP that is concentrated to 4-5x baseline platelets with an increased concentration of WBCs. See PRP Reference List.

Most studies so far have NOT been well controlled. However, Dr. Randelli (from Milan, Italy) presented the preliminary results of his prospective randomized controlled trial showing how PRP at a concentration of 4-5x baseline with increased WBCs DECREASES pain after arthroscopic rotator cuff repair and may improve healing in small and medium sized tears. Excellent work.

Several papers, posters and presentations at the meeting supported the use of PRP for cartilage restoration. Level one human data (randomized controlled trials), does not yet exist.

More soon.

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Cartilage Formation better with Platelet Rich Plasma

Here is more evidence that PRP may be helpful for cartilage regeneration.

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Platelet lysate favours in vitro expansion of human bone marrow stromal cells for bone and cartilage engineering.

Zaky SH, Ottonello A, Strada P, Cancedda R, Mastrogiacomo M.

Istituto Nazionale per la Ricerca sul Cancro, and Dipartimento di Oncologia, Biologia e Genetica dell'Universita' di Genova, Genova, Italy.

The heterogeneous population of non-haematopoietic cells residing in the bone marrow (bone marrow stromal cells, BMSCs) and the different fractions and components obtained from platelet-rich plasma provide an invaluable source of autologous cells and growth factors for bone and other connective tissue reconstruction. In this study, we investigated the effect of an allogenic platelet lysate on human BMSCs proliferation and differentiation. Cell proliferation and number of performed cell doublings were enhanced in cultures supplemented with the platelet-derived growth factors (platelet lysate, PL), either with or without the concomitant addition of fetal bovine serum (FBS), compared to cultures performed in the presence of FBS and FGF2. Both in vitro and in vivo osteogenic differentiation were unaltered in cells maintained in medium supplemented with PL and not FBS (Only PL) and in cells maintained in medium containing FBS and FGF2. Interestingly, the in vitro cartilage formation was more effective in the pellet of BMSCs expanded in the Only PL medium. In particular, a chondrogenic differentiation was observed in pellets of some in vitro-expanded BMSCs in the Only PL medium, whereas pellets from parallel cell cultures in medium containing FBS did not respond to the chondrogenic induction. We conclude that the platelet lysate from human source is an effective and even more beneficial substitute for fetal bovine serum to support the in vitro expansion of human BMSCs for subsequent tissue-engineering applications.