PRP, Microneedling, and Acne Treatment

Today I want to discuss a patient who came to see me for help in treating her acne scarring.  She is a beautiful young woman who has been very self-conscious due to acne scars on her cheeks.  The treatment that we chose was microneedling with a Dermapen, combined with platelet-rich plasma (PRP).  This is essentially a variation of what is known as a "vampire" treatment, as we take a patient's own blood to isolate the PRP and then use it to treat the damaged skin.



This therapy can be used for a so-called "facelift", or as a tool for rejuvenating the skin.
The Dermapen uses multiple ultra-thin surgical needles that rapidly and repeatedly puncture the skin to make thousands of tiny wounds as the device passes over the treated area. There is no long-term damage, and relatively minimal discomfort.  This device alone provokes the body's natural healing response, in effect leading to the production of collagen and elastin.  There is also stimulation of new capillary growth.  Healthy new skin is produced during this healing response.  In the specific case of acne scarring, these tiny needles also help to break up the fibrous and uneven scar tissue, again providing a healthy foundation for new cells.



The addition of PRP is designed to even further enhance cellular growth.  I use a combination technique, injecting some of the PRP under the skin while also applying a PRP gel topically to the affected areas.  I will not go into detail regarding how PRP works - please see some of my earlier blog entries for more information [PRP (Plasma Therapy) @ http://coloradostemcelltherapy.blogspot.com/2012/05/prp-plasma-therapy.html, and Skin Rejuvenation @  http://coloradostemcelltherapy.blogspot.com/2014/04/skin-rejuvenation_6980.html]. 


I truly believe that there are improved results by using the combination of the Dermapen with PRP.  This mode of therapy can also with other types of scarring, again by breaking up the fibrous scar tissue; it is also useful for reducing fine lines of the face, helping eliminate stretch marks, and in treating sun damage.



This patient has granted permission for me to show her before and after pictures.  She originally saw another doctor for 2 microneedling treatments, although these were not very aggressive.  She then had a total of 4 procedures with me - 2 microneedling alone, and 2 with PRP.  She is still continuing to receive treatments, as she has been very happy so far but wants even more improvement.  She is actually seeing me again today for another treatment with PRP.

Before

After 6 treatments, 4 @ MEND

Stem Cells and Multiple Sclerosis

A new Phase I trial involving the use of stem cells in Multiple Sclerosis (MS) patients is underway in a study by the Cleveland Clinic, Case Western Reserve University, and University Hospitals Seidman Cancer Center.  Multiple Sclerosis is an autoimmune disease, wherein the immune system attacks the central nervous system (CNS), both the brain and spinal cord.

So far, 2 patients have undergone the complete process, with another patient expecting to start the process soon.  In all, 24 patients with relapsing or progressively worsening MS will be in the trial over the next 2 to 3 years.  The protocol calls for harvesting of their own stem cells from bone marrow at the University Hospital, cultivating those cells at a Case Western laboratory, and then returning the stem cells to the patient intravenously at the Cleveland Clinic.

The primary focus of this study is to determine both the feasibility and the safety of such a treatment process.  In the process, the researchers will also be looking for any evidence of improvement in the patients, although the trial is not set up to actually gauge either subjective or objective endpoints.  This is a conservative study that will only look at safety parameters.  If the trial goes well, further Phase II trials would likely follow, with actual treatment endpoints as the focus.

The first patient treated in the trial, Bill White, was first diagnosed with MS about 6 years ago.  His first symptoms were fatigue and balance problems.  After a while, exercise and even walking became problematic for him, and he eventually had to stop working.  The reason for these issues is that in MS, the immune system abnormally attacks the CNS, leading to damage in the protective myelin sheaths, followed by irreversible damage to the axons and even neuronal death. The damage builds up and can progressively worsen over time, or can occur in a relapse and remission format.  The process leads to noticeable changes on MRI and the diagnosis can be confirmed by looking at the spinal fluid.  Mr. White had the characteristic changes on a scan of his brain in 2007.  He has also since undergone treatment with 2 different drugs without seeing much benefit, if any, while subjecting him to a variety of side-effects.

After enrolling in this trial, his stem cells were harvested in March.  The stem cells were cultured in the lab for months, and they were eventually injected into his bloodstream in June.  Mr. White saw changes very quickly.  He stated  that "I used to have to use my left arm to lift my left leg up.  Now I can lift it up on my own", meaning without the assistance of his arm.  And although he still tires when walking, he does so less quickly now.  In addition, his vision has improved from 20/50 to 20/20.  Objectively, a recent MRI showed no new lesions in his brain.  The proposed mechanism of action for the stem cells is in modulating the immune system, causing a decrease in the immune attack on the CNS.  Also, the stem cells may be promoting the healing and regrowth of damaged tissues.

Other Phase I trials looking at stem cells and MS will soon be underway in Spain, China, and Iran.  These are exciting times for sure, and the idea that a patient's own stem cells could help with the treatment of MS is truly amazing!

Stem Cells and PRP Go Mainstream

I was glad to see stem cell therapy and PRP injections getting some love from the mainstream media recently - courtesy of AARP,  There was an article in AARP The Magazine from May, 2014, titled "Arthritis:4 Treatments to Try Now", in which the author recommends injections to help with symptoms of osteoarthritis.

Osteoarthritis is the most common form of arthritis, essentially wear and tear on the joints.  Over time, the protective cartilage wears down, eventually leading to pain as the bones rub against each other.  There are few treatment choices, most of which can have detrimental side effects.  Anti-inflammatory medications, or NSAID's (such as ibuprofen and naproxen), can be used to help with the pain, but their use for extended periods can be dangerous for multiple reasons. [I plan to devote an entry on this exact topic at www.ColoradoOnTheMend.blogspot.com soon.]  Exercise and physical therapy can also help, but their effectiveness may be diminished due to pain interfering with a patient's ability to proceed long-term.  And finally, there is the prospect of surgery - either in an attempt to repair damaged cartilage or with joint replacement.  Again, there are serious side effects and potential life-threatening complications with surgery, and there is no guarantee it will work.

That is why PRP and stem cells show such promise - few side effects and a great potential upside. The author mentions a great article from January, 2014,  in the Journal of Bone and Joint Surgery titled  "Adult Human Mesenchymal Stem Cells Delivered via Intra-Articular Injection to the Knee Following Partial Medial Meniscectomy", wherein patients who received stem cells had increased meniscus volume and a significant reduction in pain compared to the control group.  Here is the direct link to that study - http://jbjs.org/content/96/2/90 .  Again, we have seen these results with our own patients, and continue to find ways to improve outcomes even more.

The AARP article also mentions newer medications, knee distraction (a procedure involving an external metal frame applied around the joint; the frame must be in place for months, with extensive rehab involved), and cartilage replacement as other therapies to try.

Here is the link to the article - http://www.aarp.org/health/conditions-treatments/info-2014/arthritis-treatments-to-try-now.html

Stem Cells in Stroke Recovery

In the April 8, 2014 edition of the journal Neurology, neurologist Steven Cramer, M.D. and a team from the University of California - Irvine published a meta-analysis reviewing 46 preclinical studies looking at the efficacy of stem cells in treatment of ischemic strokes.  The researchers found that 44 of these studies showed significantly improved outcomes over control therapies.

Of particular interest is the fact that the effects of the stem cells on functional recovery were quite beneficial regardless of how they were delivered to the patients, the overall dosage/amount of cells given, and even the timing of treatment in relation to the stroke event.  As examples, there were improved outcomes when stem cells were given a month after the stroke, and whether given via a blood vessel or injected directly into the brain.  These studies were based mainly on stem cells derived from bone marrow, but adipose (fat) derived stem cells should at least show similar promise, if not more.

Of note, the stem cells that are administered do not appear to actually develop, or differentiate, into neural cells.  Thus, the stem cells are not actually replacing the damaged cells by turning into new neural cells.  Instead, the stem cells modulate the immune system and help the overall healing process.  Stem cells release a wide array of growth factors and chemicals that help to stop damage already occurring in cells, increase the growth of new cells, stimulate growth of a new vascular supply, protect cells at risk, and improve the connective tissue that supports the neural tissue. It is in these ways that the outcomes are greatly improved.

Although all of the studies looked at were preclinical, meaning not actual treatment or trials on humans, the overall results are quite compelling.  The next step will be clinical trials on human patients that will then start to define the best practices for the use of stem cells, including ideal timing and dosage.

The Biology of Wound Healing

I have received questions in regards to the mechanism of wound healing, and how stem cells play a part.  This entry is (hopefully) an easy-to-understand lesson in the biology behind the process.  Please feel free to pose any other questions to me and I will do my best to answer!

I will focus on the healing process of the skin, or the dermis.  In general, there are four overlapping phases to dermal wound healing: 1. coagulation/hemostasis  2. inflammatory response   3. cell proliferation   4. remodeling. 

Hemostasis starts once the initial injury occurs, compromising the integrity of the underlying blood vessels.  As blood escapes from these vessels, platelets interact with collagen and other extracellular matrix substances.  It is these stimulated platelets that begin the clotting cascade and release clotting factors and inflammatory cytokines. 

The inflammatory phase starts within hours of the initial insult, mainly as neutrophils enter the fibrin clot in response to the cytokines.  They are followed by leukocytes and macrophages which work together to neutralize foreign substances and help to sterilize the wounded tissue.  It is also during this phase that stem cells are activated by pro-inflammatory mediators.  Stem cells modulate the immune response and can help inhibit the activity of mast cells and natural killer cells. In this way, stem cells can attenuate the acute immune response.  The inflammatory environment also stimulates stem cells to upregulate prostaglandin E2, favoring dermal tissue regeneration.  In summary, stem cells favor wound healing over inflammation, while helping to promote functional regeneration during the next phase.

The proliferation phase begins as these immune cells recruit local reparative cells (including more stem cells) from the surrounding area to form what is called granulation tissue.  This granulation tissue is well-vascularized, meaning it has a substantial blood supply, and acts as a scaffold for tissue regeneration.  Eventually this is what allows for the wound bed to heal and close off.  Stem cells help encourage the construction of a viable vascular supply, through the release of many growth factors.

The process concludes with the remodeling phase, wherein cells called fibroblasts help reorganize the extracellular matrix to reinforce the early granulation tissue and also to produce proteins that help regenerate the skin tissue.  Stem cells express certain factors that help in this phase to promote growth of healthy and functioning dermal tissue, tissue that resembles uninjured tissue as opposed to scar tissue.

By understanding this entire process and the role stem cells play in it, we can then use a patient's own stem cells to help in the acute healing process.  Stem cells directly applied to or injected into a wound can help with healing through multiple mechanisms, adding to their own injury response.  There is also accumulating evidence that stem cells given systemically through an IV will find the injured area through complex signaling and still impart a regenerative effect.

I hope this explanation is not too scientific and not overly filled with "medicalese".  If so, please let me know....

The Future of Medicine

The future is looking brighter and brighter when it comes to stem cells and medicine.  Stem cells will eventually play a pivotal role in saving lives and curing diseases, along with treating injuries and regenerating our bodies.  We are in the early stages of both research and functional use in medical practice.


One of the most intriguing and exciting realms is in bioprinting, or the production of 3-D tissue/organs.  Bioprinting involves growing a patient's stem cells in a growth medium in order to have them multiply, then using them to form a "bioink" made out of cell aggregates.  This bioink is next placed into cartridges that are essentially syringes with long extension nozzles for printing.  Specific software then drives the bioprinter to deposit the bioink cell aggregates into very precise layers.  The layers are stacked one upon another and interspersed with hydrogel, a water-based substance that is used as a temporary mold to hold the structure together.  The printed tissue is then allowed to grow, and as it matures the hydrogel is removed (usually within the first 24 hours so that this material does not interact with the cells).  The finished tissue product can then be used in medical research or as an actual transplanted material for the patient. 


Bioprinting is different from traditional tissue engineering that involves culturing cells and subsequently seeding them onto molds or scaffolds.  In this more standard model, the mold is designed to look like the intended organ or tissue and is biodegradable.  Once the cells mature and produce their own matrix the mold is then removed.  It is the timing of the scaffold elimination that is very critical.  If removed too quickly the tissue structure can fail.  If it degrades too late in the process the tissue may grow into it in a manner that inhibits proper tissue growth and can lead to scarring in patients.


This technology is still in its infancy, as the ability to print tissues has been limited to more basic tissue types.  Flat structures such as skin, cartilage, and muscle have been successfully engineered, while tubular structures (blood vessels, trachea, etc.) are a bit more difficult to create.  Hollow, non-tubular organs are the next most difficult, such as bladder, stomach, or uterus.  And finally, the more solid organs are the trickiest, including the heart, liver and kidneys.  These more complex organs involve more cell types, more intricate layering of these cell types, and extensive vascular structure as well. 


It is these solid organs that are truly the next frontier in the world of bioprinting.  There is some debate as to whether or not we will ever be able to truly create an entire heart or kidney due to the complexity of such organs, and thus the difficulty in matching the minute details as they exist in a functioning human body.  We might be able to build a similar organ that functions in the same manner but has differences, most notably in being a simpler design.  Another possibility is printing smaller tissue patches that could then be used to repair or augment the body's damaged or diseased organs.  An example is engineering a cardiac muscle patch that could then be transplanted to replace an area of heart muscle damaged after a myocardial infarction, or heart attack.


There will no doubt be a time when bioprinted organs take away the need for current transplant surgeries that involve risk to both the recipient and the donor, as well as the potential for rejection and need for immunosuppression.

Skin Rejuvenation

Platelet-rich plasma (PRP), as I have discussed in previous posts, has the ability to promote healing and rejuvenation of various tissues.  The growth factors that are secreted have shown promise in the production of collagen and other matrix components through the activation of fibroblasts (the most common type of cell in human connective tissue, actually an activated stem cell) in the skin.


An article from the Journal of Drugs in Dermatology, 2010 May; 9(5):466-72, by Redaelli et. al., involved a three month study with 23 patients who received injections of PRP in the face and neck in an effort to promote skin rejuvenation.  The patients each received three treatments over the course of the study, with documentation and imaging before and after each session with a final follow-up one month after the last treatment.  The injections were given at specific points in both the face and neck, identical in all patients and with every treatment.  The study used the following imaging techniques: dermascope, digital camera, and a comprehensive state-of-the-art imaging system with dedicated medical imaging software.  The results were evaluated by a special "spider improvement score", a patient's satisfaction score, a doctor's satisfaction score, and a photograph score. In addition, a definitive graduated score was calculated for each patient.  Overall the results were satisfactory and showed promise.  Also, there were no serious or persistent side-effects.  The authors felt like this was a useful therapy for skin rejuvenation.


As a later follow-up to this, a group of researchers (Kim, et.al.) in Korea published an article in the Annals of Dermatology, 2011 Nov.; 23(4): 424-31, evaluating the actual effects of PRP on dermal fibroblasts.  This study looked at the effects of PRP on matrix protein synthesis, collagen production, and fibroblast cell proliferation.  PRP showed an increase in the expression of type 1 collagen, MMP-1 protein (matrix metalloproteinase), and mRNA in human dermal fibroblasts, thus verifying that PRP does promote tissue remodeling.  The researchers hypothesized that the PRP may promote extracellular matrix remodeling through the removal of photo-damaged components and through the induction of new collagen synthesis by the fibroblasts, which in turn proliferate by their stimulation. 


It is felt that PRP can be beneficial as either a stand-alone procedure, or as an adjuvant therapy with lasers for skin rejuvenation.  We are currently interested in comparing the results of both a superficial application and injections, or possibly even a combination of both.  In addition, the use of stem cells might improve the results even more, although at a higher dollar cost.

Meniscus Knee Surgery and Stem Cell Therapy

The latest in orthopedic surgery and stem cell therapy was discussed in a study that appeared in the January 2014 issue of the Journal of Bone and Joint Surgery (Volume 96, Issue 2). The study, whose full title is "Adult Human Mesenchymal Stem Cells (MSC) Delivered via Intra-Articular Injection to the Knee, Following Partial Medial Meniscectomy", followed groups of patients who received a single injection of stem cells after knee surgery.

The study was designed with three groups of patients: those receiving a "low-dose" of 50 million stem cells within 7-10 days after surgery, those receiving a higher dose of 100 million stem cells, and a control group receiving sodium hyaluronate without stem cells.  The surgery performed is called a partial meniscectomy, a procedure that is used to treat tears in the meniscus by removing all or part of the torn cartilage.  There were a total of 55 patients in the study.


The key findings of this study were as follows:
1. There was no abnormal/ectopic tissue formation.
2. There were no "clinically important" safety issues identified.
3. There was "significantly increased meniscal volume" by MRI in 24% of the "low-dose" patients, and 6% in the higher dosed patients at one year.  There was no statistical increase in either group at 2 years.  A "significant increase" was defined as at least a 15% increase.
4. There was no statistical increase in meniscal volume in any of the control group patients.
5. Stem cell patients with osteoarthritis showed a reduction in pain; control group patients experienced no decrease in pain.


These findings are consistent with what has been found in the literature and with the results we have experienced in our practice.  The stem cells show improvement both objectively (increased meniscal volume by MRI) and subjectively (decreased pain).  It is interesting that this study was performed on post-surgical patients, as the stem cell therapy might have eliminated the need for surgery if performed alone.  However, it does show that stem cells can be beneficial for those patients who are determined to have surgery.