For most women, a tiny pimple on the face is enough to ruin their day. Or week. Even the slightest imperfection that may have a 1% chance of getting noticed by others will freak them out. For these women, Melasma is their darkest nightmare. It’s a pretty common issue, a result of exposure to sun, that causes brown patches on the face. Permanent patches, I should add.
If you’re suffering from Melasma, the road to “recovery” usually looks like this.
- You hope that it’ll fade away.
- Your friend suggests you try apple cider vinegar and lemon juice treatment.
- Slightly disappointed.
- You visit a dermatologist who’ll prescribe a bleaching cream (hydroquinone or similar).
- Full-on disappointment.
- You Google the hell out of the topic.
- Concealers and makeup becomes your best friend.
At this point, no one can convince you there is a treatment for getting rid of melasma. Trying more and more treatment only runs the risk of making the condition worse. So what would you do?
Platelet-Rich Plasma For Melasma
What about Platelet-Rich Plasma For Melasma?
According to recent Turkish and Malaysian studies, Platelet-Rich Plasma is showing great promise for melasma. The one good thing about PRP for Melasma is the fact that PRP won’t make the condition worse unlike IPL, fraxel or other treatments. So that’s one of the treatment you can confidently try without worry. It’s like getting a natural facial treatment that has a whole lot of potential benefits even if it didn’t help cure melasma.
PRP injections work by supplying growth factors to reduce the pigmentation. And being an independant treatment with no downtime, it can be done in conjunction with conventional treatments for melasma to add and enhance the effects. There are more than 30 bioactive substances in Platelet-Rich Plasma that has separate roles like increasing skin volume and adding new blood vessels to name a few.
Platelet-Rich Plasma with Microneedling
This is the most common combination for Platelet-Rich Plasma therapy. Here’s a video of Dr. Michael Somenek performing PRP injection on a patient of his immediately after microneedling. The combination is known to have produced results for a lot of varieties of skin pigmentation issues that it’d not be wise for anyone to ignore it for melasma, especially when creams and peels didn’t help. More important is PRP’s ability to stimulate collagen production in the area so it tightens the pores and makes your skin glowing.
Why Platelet-Rich Plasma?
PRP is primarily a healing vehicle. It needs to be injected into the membrane below the skin. The way it works is by supplying the underlying skin membrane with collagen and tenascin stimulated by the transforming growth factors in PRP. These growth factors also promote formation of new blood vessels that in some cases results in disappearance of spider veins.
The released growth factors (mainly platelet derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and transforming growth factor-beta (TGF-ß)) can stimulate proliferation of fibroblast and epidermal cell, and collagen synthesis. In addition, the transforming growth factor-beta (TGF-ß) has been proven to inhibit melanogenesis — or reverse skin pigmentation — the exact opposite effect of exposure to UV-B radiation.
Typically, patients see excellent results with 2-3 PRP injections in the first 3 months. And clinical studies have shown that it will maintain after 6 months.
However, Melasma is known to recur even after successful treatments. So you must take precautions against it by using sunscreen with broad-spectrum protection and an SPF of 30 or higher. And avoid skin care products that are harsh as they can exacerbate melasma.
Cindy is a career woman. So when she became pregnant for the first time, she was confused about which aspect of her life had higher priority – her work or taking care of her growing body. Not wanting to drown in that confusion, she kept herself busy with her work all day while snacking every little free time she had. This meant she was putting on a lot of weight, fast. Occasionally, her more experienced sister would remind her to apply Bio Oil on her growing tummy before bed, but she was too exhausted to actually do it. Except maybe for a few nights.
It wasn’t until after she delivered her baby that she realized her folly – her belly now looked like a road map.
What Works For Stretch Marks?
Sure, there are a variety of topical treatments, the ones with cocoa butter are the trend, but they’ll hardly affect severe stretch marks. They perform better when used as preventive measures. Because fully developed stretch marks are rarely skin deep. The stretching occurs on the layer underneath the surface called dermis. And the inability of the surface layer (epidermis) to keep up with the stretching is what’s causing the appearance of deep roads of stretch marks.
One way to “cure” stretch marks or at least the appearance of stretch marks is to make the skin surrounding the stretch marks a level closer to the stretch mark itself. This can be done by various minimally invasive “scarring” technologies like microdermabrasion, microneedling and CO2 fractional laser.
But You Said Platelet-Rich Plasma For Stretch Marks, Didn’t You?
Yes. But you see, platelets can only supply growth factors wherever healing is initiated. So unless healing is initiated or is still ongoing (not in the case of a fully developed stretch mark), the injected Platelet-Rich Plasma may not be able to produce it’s excellent results.
That’s why in forums you can hear a lot of advice from doctors who claim Platelet-Rich Plasma can’t help stretch marks. In fact, that’d be the first thing I’d say if someone asked me.
However, what if we could artificially initiate the healing? Not only in the outer epidermis layer, but also in the underlying dermis layer too? Now, that’s an excellent opportunity to put the growth factors in Platelet-Rich Plasma to good use, wouldn’t you agree?
Platelet-Rich Plasma For Stretch Marks
Actually that’s exactly how hundreds of thousands of happy men and women get rid of their stretch marks, around the world.
Enter PRP Microneedling
PRP microneedling is nothing but swapping Vitamin C that’s used in traditional microneedling with Platelet-Rich Plasma. This is traditionally called Platelet-Rich Plasma facial – due to the fact that you’re essentially spreading blood components over your face. This is a particularly effective treatment for the face. But it can provide even better results for stretch marks (probably the most effective treatment for stretch marks.)
Here’s why this particular combination really works:
- Getting to the root of the situation
With micro-needling, what we’re actually doing is punching some holes on both the outer epidermis layer and the inner dermis layer of the skin. These holes are so micro that it restores back to normal within minutes or hours. However, during the time it’s open a healing response is triggered. The very act of triggering a healing response in the inner dermis layer means there’s going to be some improvement on the stretch marks – as that’s where the source is. That’s probably why doctors recommend micro-needling for stretch marks over any other treatments. The procedure also removes unwanted, half-dead cells from the outer skin causing the stretch marks to appear less deep.
- Accelerated Healing With PRP
PRP’s job is to accelerate the healing response triggered by the micro needles, and it must do so during the time it’s open. So immediately after the micro-needling, a concentrated gel of PRP is applied. And massaged well enough for the platelets to actually seep through the holes. These platelets first stop the micro-bleeding caused by the microneedles and then the growth factors in the platelets trigger the production of a substantial amount of collagen. Now, collagen’s primary role is replacement of dead skin cells. Which means, it’ll replace all the dead, broken and torn skin cells in the entire area. The result is fresh new skin in the areas of the stretch mark causing it to actually shrink in size and look more rejuvenated.
Why Platelet-Rich Plasma?
Platelet-Rich Plasma is a powerful healing component. That’s why it was invented in the first place. In 1987, surgeons found that autologous platelet-rich plasma and red blood cell concentrates diminishes the cost of healing for cardiac surgery — meaning faster, efficient and natural healing for patients. Now, the same force that heals a cardiac surgery also can also cause rejuvenation of our body — whether it’s the skin or any other organ in the body. We’re only beginning to peel layers of healing potential found in Platelet-Rich Plasma. A 2015 chinese study about growth factors in PRP says it can even heal bones. They’re not the only ones. Here’s another study of PRP for bone grafts and they found it helps too.
So it’d be outright foolish to not use such a potent, natural healing agent for skin rejuvenation purposes. And micro-needling seems to be just what Platelet-Rich Plasma needs to exercise its healing powers. It’s much better than stockpiling tons of topical products that might “cure” stretch marks — scar creams, retinoids, and peptides.
Platelet-Rich Plasma For Stretch Marks
The More Earlier The Better
In healing, studies show platelets have much better efficiency when they are introduced right after the wound initiation. The same is the case for stretch marks. As soon as you see those marks, it’s better to head straight to the clinic and get a Platelet-Rich Plasma + Micro-needling session to heal it. The longer you wait, the more harder it gets to wipe them off. So stop experimenting with topical creams – they’re meant to be used as preventive measures.
Platelet-Rich Plasma has a proven record for healing soft-tissues and other living tissues. But can it actually heal the bones itself?
This could mean PRP, when applied to an affected area whether it’s an elbow joint or knee or back bone area, actually heals everything within it’s reach including the bones. Is that really why PRP actually works?
Platelet-Rich Plasma For Bone Healing
Bones are not just lifeless matter attached to living tissues. It’s as much living as the tissues themselves. And just like the tissues, it’s constantly changing too. The old bone cells are broken down and replaced with new ones in a three-part process called bone remodeling the involves resorption (digestion of old bone cells), reversal (new cells are birthed) and formation (new cells turn into fully formed bones).
This process, just like any other biological processes in the body, requires hormones and growth factors. Some of the names include parathyroid hormone (PTH), calcitriol, insulin-like growth factors (IGFs), prostaglandins, tumor growth factor-beta (TGF-beta), bone morphogenetic proteins (BMP), and plain old cytokines. For this discussion we need to remember only one thing: a large cytokines and growth factors are involved in bone remodeling process.
Which means we accelerate the bone remodeling process by supplying these cytokines and growth factors as suggested by studies like this, this, this, this, this and this.
Why Platelet-Rich Plasma?
Autologous Platelet-Rich Plasma (PRP), being completely “whole and natural” can more closely simulate a highly efficient in-vivo situation that anything else out there that are made up of artificial recombinant proteins. In PRP, we are taking advantage of the biological benefits of growth factors whose functions we know as well as those we do not know of yet. From the 15+ factors we know are in PRP including platelet derived growth factor (PDRF), transforming growth factor-beta (TGF-beta), platelet factor 4 (PF4), interleukin 1 (IL-1), platelet-derived angiogenesis factor (PDAF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), platelet-derived endothelial growth factor (PDEGF), epithelial cell growth factor (ECGF), insulin-like growth factor (IGF), osteocalcin (Oc), osteonectin (On), fibrinogen (Fg), vitronectin (Vn), fibronectin (Fn) and thrombospontin-1 (TSP-1)… we’re actually supplying a “holistic” set of nutrients for healing that cannot be mimicked by those obtained artificially.
Platelet-Rich Plasma For Bone Healing
Organic Fertilizers For The Body
The PRP difference is like adding chemical fertilizers versus organic fertilizers on plants. Chemical fertilizers are rich in essential nutrients that we know are needed for crops. On the other hand, organic fertilizers supply nutrients not only to the plants but also to the soil, improving the soil structure and tilth, water holding capacity, reduces erosion as well as promote slow and consistent release of nutrients to the plants itself.
Clearly, organic fertilizers are better, aren’t they?
Platelet-Rich Plasma are like organic fertilizers for our body.
Bonus: Strong Antimicrobial Properties
It seems that the Platelet-Rich Plasma’s healing function has synergistic function to anti-microbial properties. A new study confirms that using Platelet-Rich Plasma in surgeries may have the potential to prevent infection and to reduce the need for costly post-operative treatments.
That’s a nice bonus for the organic fertilizer of our bodies. Perhaps, there are more. So why wouldn’t anyone not take advantage of them?
The scope of Platelet-Rich Plasma is growing as the scientific community continues to unearth its inherent properties. PRP is an unignorable, and unavoidable component of healing.
To understand why stem cell platelet-rich plasma or co-transplantation of Adipose-derived mesenchymal stem cells and PRP, is such a remarkable idea in regenerative medicine, let’s spend a little time looking at the mechanics of PRP.
Platelet-Rich Plasma’s Role As Repairmen
The one thing that makes Platelet-Rich Plasma a hero in several fields (if not all) of medicine is the fact that the diverse growth factors in it are able to stimulate stem cell proliferation and cell differentiation (the factors that determine effective tissue regeneration and healing) on any part of the body.
These growth factors are abundant in the blood and act as the natural repairmen of tissues.
In the perfect scenario, there’s plenty of blood flow to every part of the body and these “repairmen” are always on-call to address any healing needs that may arise. However, if the injured area has a poor blood supply — especially areas that are constantly move like tendons, ligaments and joints — demand for these repairmen can outgrow supply. Meaning, healing (or regeneration of tissues) is put on hold till further repairmen are available.
The train of Platelet-Rich Plasma then arrives with enough of these repairmen to warrant resumption of healing.
There’s another part of this picture we haven’t talked about so far: stem cells.
As far as Platelet-Rich Plasma and it’s growth factors are concerned, they are mere repairmen. They can’t do the work by themselves. They need the basic raw materials to work with. And that raw material here is the stem cells.
Stem cells are the ones actually being regenerated to form new tissues for healing.
Stem Cells As The Raw Materials For PRP
Stem cells are the only raw materials that PRP works with for regeneration. These are like the fundamental building blocks of all other cells. These cells can be can be guided into becoming specialized cells under the right conditions.
In addition, they can also divide themselves to form new stem cells or new specialized cells.
So for Platelet-Rich Plasma to work well, it needs to be applied to an area with lots of stem cells like the heart, liver, blood vessels etc. Incidentally Platelet-Rich Plasma’s healing properties were first discovered by cardiac surgeons who played with concentrated blood for faster healing of heart after surgery and it showed tremendous promise because stem cells are abundant in heart tissues.
But what if healing is needed in an area where there are not much stem cells?
With the new developments in stem cell technology that can be solved too. Because now we can supply the stem cells to areas where there are less like the joints, ligaments and tendons. For this, scientists usually use “mesenchymal stem cell” or MSCs. These are cells isolated from stroma and can differentiate to form adipocytes, cartilage, bone, tendons, muscle, and skin.
The most easiest way is to harvest it from adipose tissue or fat that we call Adipose-derived mesenchymal stem cells or ADSC.
Stem Cell Platelet-Rich Plasma
Supplying Both PRP And Stem Cells For Regeneration
In regions with hypoxia (poor blood supply) like joints, meniscus tissue, rotator cuff, spinal discs etc the supply of platelets (and therefore growth factors) as well as the stem cells are limited. So what if we supplied both the stem cells and Platelet-Rich Plasma for triggering the regeneration process?
That’s the question these Japanese scientists answered in their research. Here’s another group of scientists who took on the same challenge.
They used Adipose-derived mesenchymal stem cells (ADSC) which is known for their ease of isolation and extensive differentiation potential. These researchers noted that these stem cells often can’t survive in areas of local hypoxia, oxidative stress and inflammation – thereby making them ineffective. However, when Platelet-Rich Plasma (or thrombin-activated PRP) is added to ADSC, it kept them alive for prolonged periods and the growth factors in the Platelet-Rich Plasma triggered cell differentiation and proliferation more easily.
Why This Exact Combination Is The Future
Done this way, both Adipose-derived mesenchymal stem cells (ADSC) and Platelet-Rich Plasma are raw materials for healing that’s already available in plenty in almost every one (there are exceptions of course). That means, for complete healing to take place this combination treatment, still in it’s very primitive stage of development, may have the potential to replace expensive synthetic drugs that carry complex unexplained side effects. The procedure takes our body’s natural healing agents — stem cells from body fat and PRP from blood — and then inject it inside knee or other joints (or other areas where they are insufficient) for regeneration.
Isn’t that like the most wonderful thing ever?
Whether it’s cartilage cell, or a bone cell, or a collagen cell for ligaments and tendons that needs to be healed, all you need is a same-day procedure by a local, but specialized doctor, using the natural ingredients of the body.
I believe this special combo is a huge win for Platelet-Rich Plasma.
The Challenges For Growing Adoption Of This Treatment
We know Platelet-Rich Plasma has safe, yet high-speed recovery potential with it’s multiple growth factors. And it is effective in regenerative healing of cartilage injuries – the most toughest injuries to heal – as well as Osteoarthritis. However the challenges are Platelet Quality. We need to somehow ensure the Platelet-Rich Plasma quality is uniform. Currently it varies from two to several fold above baseline concentration based on donor’s physical condition.
Next we need to identify the exact PRP growth factors that promote ADSC proliferation. Scientists believe growth factors such as basic fibroblast growth factor (bFGF), epidermal growth factor, and platelet-derived growth factor stimulate stem cell proliferation while some growth factors under certain conditions are known to inhibit the process.
The percentage of PRP matters too. 5 percent, 10 percent, 15 percent and 20 percent Platelet-Rich Plasma in ADSC are tested by scientists.
The Only Treatment In Modern Medicine For Cartilage Regeneration
The bottom line is that Stem Cell Platelet-Rich Plasma or ADSC + PRP procedure is the only treatment in modern medicine that has showed cartilage regeneration. So it’s too important to ignore. And it could one of greatest advances that science has brought to the millions of people suffering from serious pain in their joints, knee and spine as well people suffering from all kinds of tendon diseases and injuries.
The time it takes to draw a patient’s blood, add a little citrate, and use a centrifugal machine with a PRP kit is only 15-20 minutes. This is the amount of time needed to create Platelet-Rich Plasma, or PRP. This can then be used for many purposes, using speeding up a patients recovery.
PRP is by far the best healing agent that has growth factors and platelets to help with the healing process, which is also completely free and natural to obtain.
What are The Advantages Of Using PRP Correctly?
It is easy to create PRP simpy by placing blood in a centrifuge, but it can have very little, if any, platelets, and would otherwise be useless. However, with the right equipment, you can make PRP with up to 7x the amount of platelets. This can be amplified by using fat tissue and collagen fibers to create a PRP matrix.
7 Popular PRP Treatments
- Facial Treatments
Many skin centers are thriving due to being one of the first to adopt PRP therapies. With the lack of side effects or down time, it became incredibly popular. These treatments include wrinkle reduction, skin rejuvenation, dark circle and bag erasure, rosacea treatment, and even lip augmentation.
One popular and generic treatment option includes combining PRP and a treatment known as microneedling. When this is applied, it’s effects are similar to facelifts, for far less cost and side effects.
- Hair Loss
PRP growth factors can be beneficial when it comes to reversing non-genetic early stage hair loss. Despite there being a huge market for this, almost no practitioners actually utilize it. Many clients have seen promise after hair thinning, and many have seen beard regrowth over time.
- Arthritis and Cartilage
Arthritis treatments alone cost patients 6.4 billion dollars in 2013 for the US alone, with projections of up to 9 billion by the end of the decade. However, unlike the other treatments, PRP is seen as the only treatment that can not just reduce symptoms, but also regrow the cartilage. One of the most popular examples would be treatments for Temporomandibulaar Joint Osteoarthritis.
- Anti-aging Properties
When it comes to the anti-aging market, there are a endless number of treatments and procures available. Yet, none of them even stand close to the effectiveness of PRP therapy. PRP combined with Microneedling can ve highly effective for strech marks, acne scars, breast augmentation, and even skin conditions like Lichen Sclerosus.
- Pain Relief and Musculoskeletal Healing
There are a ton of treatments in this category, with many of them being incredibly more effective than leading treatments. These include healing Rotator Cuffs, Tennis Elbow, Achilles Tendonitis, Patellar Tendonitis, Back Pain, Hip and Pelvic problems, Degenerative Disc Disease, Golfer’s Elbow, Labaral Tear, Brusitis, neck pain, avascular Necrosis, and even pain related to nerve regeneration.
Almost all of these treatment, as opposed to those in other categories on this list, also use ultrasound guidance when injecting the PRP directly into the affected tissue. This can allow patients to see fantastic results in as little as 2 weeks.
Ovarian Rejuvination is where PRP is injected directly into a woman’s ovaries. This is meant to help reverse menopause and help lower fertility issues. This treatment can even be used for sexual regeneration. Although similar, this treatment is not the same as other treatments where PRO is injected into the vagina, and is supposed to treat looseness, dryness, low sex drive, and incontinence.
- COPD (Chronic Obstructive Pulmonary Disease)
Allergies, asthma, and COPD are among the growing list of things that PRP is being used as a treatment for. For this to work, the PRP is mixed with a saline solution, and then, using a nebulizer, is inhaled, and helps to regenerate the lung tissue.
Although it can take up to 2 months for patients to see the effects, many are seeing improvements. Almost 1 million people suffer from COPD a year, so anything that can help treat the condition is beneficial.
PRP has been trending rather well in the recent years, and seems to be here for the long term. Not only it is a fully natural remedy, but it is one that works better than most or all traditional treatments. Many like it due to the fact that there are few side effects, it only takes a short amount of time, and there is no recovery period.
PRP has been adopted by thousands of clinics and practices throughout the US and the world. The demand for these treatments have been increasing almost faster than practices are choosing to provide them. Many patients are even willing to travel long distances just to receive these treatments.
So are you providing PRP treatments yet?
Since it is a new science, many people are skeptical about Platelet-Rich Plasma, otherwise known as PRP. There are some studies out there that state that PRP work no better than a similarly administered placebo, but there are many other studies and doctors that claim that PRP works and works well. This also works well at a much lower cost and less side effects, than traditional medicine.
One branch where the skepticism is loud and clear is podiatry, which deals with feet and ankles. Trying to combat this skepticism can help many surgeons to lower complication rates, improve patient satisfaction, and have better outcomes. For instance, here is a list of cases where PRP has been effective for the feet and ankles.
- Plantar Fasciitis
PRP has become rather common as a treatment for Plantar Fasciitis, with many studies to prove the efficacy of this treatment. For instance, Dr. Daanial Kassicieh or Sarasota Neurology claims that PRP is one of the most effective treatments for this condition, and that PRP is actually fully cure it. Many of his patients have avoided surgery just by utilizing PRP therapy.
This is done with no down time, no rehabilitation, and no side effects. This woud explain why plantar fasciitis is the 5th popular medical condition treated by PRP. This can be explained by over 3 million people that are diagnosed with this and no other treatment really works for it, besides, in fact, PRP.
- Archilles Tendonitis
This is another condition that can be fairly hard to treat, and gets worse over time unless healed. Many surgical approaches are often trickey and generally do not end up with good results. Because of this, the main treatment option is simply to give patients corticosteroids to reduce the pain, but really nothing else to treat the symptoms.
However, there have been many studies done that have shown that PRP is a lot more effective, including that from the European Foot and Ankle Society. This means that PRP is safer and more effective alternative than any other treatments available.
- Diabetic Foot Ulcers
Diabetic foot ulcers can be troublesome, especially when they do not heal or heal properly. Over 2.5 million Americans with diabetes who suffer from these ulcers. About 11% of these cases may need amputation of their affected limb. However, some studies have noted that just one injection of PRP and a topical solution bi-weekly started to heal the ulcers in just 8 weeks. Topical PRP also has been shown to work better than anti-septic creams as well.
- Regenerating Bones
Bone regeneration is most commonly needed in food and ankle area. Although mechanical stabilization works best, the utilization of PRP has been surprising. PRP helps with healing bones and soft tissue at the damage site. According to a recent systematic review of 64 articles, the conclusion was to include more PRP therapy into the healing of foot and ankle bones.
The science behind this is solid, for bone or tissue to form, three things are needed in the area:
- A scaffold for the growth to take place
- Biological stimulants to signal proteins
- Stem cells that provide bone building potential
All three of these are crucial for bone formation.. PRP can provide at least two of these, so there is no reason to ignore it when it comes to bone regeneration.
- Ankle Sprains
This is an incredibly common condition, and can be effectively treated by using PRP therapy. In one randomized controlled trial, researchers studied the effects of PRP injections on athletes with ankle sprains. This study showed that not only did PRP reduce the healing time by 20 days, but that they also experienced much less pain. This can reduce the recovery period from 6 weeks, for just about 2 or 3 weeks.
Immobilization is Vital
When it comes to foot and ankle related injuries, one thing that really cannot be avoided in rest and rehabilitation. This is true regardless of whether PRP is administered. Because of this, many of the studies that shows PRP to be ineffective often don’t use rest and rehabilitation, and that alone can be an issue.
PRP is in no way a magic pill. All foot injuries need rest and rehabilitation in order to properly heal. With these two combined, it can drastically reduce healing times.
How can Foot and Ankle Surgeons Benefit?
Using PRP in foot and ankle injuries is not going anywhere, so utilizing it would be the best way to go. Test it out with your patients, and try using platelet-rich plasma therapy instead of simply prescribing pills or doing costly surgeries. Your patients will thank you in the end.
Musculoskeletal tissue injuries and degeneration are common and debilitating for a high number of patients (Brooks, 2006). Unfortunately, endogenous musculoskeletal tissue regeneration is limited in many cases and may be affected by inflammation and the degree of damage. For example, most fractures of long bones heal spontaneously, whereas large segmental defects fail to heal. Additionally, although articular cartilage has almost no intrinsic reparative potential, tendons and ligaments may heal, but often with inferior properties. The high prevalence of these injuries has led to significant investment in the development of new therapies to enhance healing and augment current surgical interventions. Often the goal is to mimic and recapitulate the natural healing cascade and developmental process by transplantation of tissue-specific stromal and progenitor cells or by endogenous manipulation to enhance the native repair capacity of cells.
There has been a continuing increase in the number and type of stem and stromal cells being pursued in human clinical trials for treatment of musculoskeletal injuries (Steinert et al., 2012). Most approaches in this area are based on ex vivo-expanded mesenchymal stromal cells (MSCs) derived from bone marrow (BM). Originally identified and characterized by their multilineage differentiation potential in vitro, multipotent capabilities of MSCs in vivo have not been clearly demonstrated to date, particularly because of the lack of methods to identify and define differentiated populations (Nombela-Arrieta et al., 2011). Central to recent progress in the field has been the understanding that stem and progenitor functions of MSCs may not be the key attribute that mediates tissue repair. In addition, there is outstanding controversy over the terminology of exogenously supplied MSCs as stromal cells, and various terms, including medicinal signaling cells, have been proposed to more accurately reflect their therapeutic function in vivo (Caplan, 2017). Nevertheless, the therapeutic benefit of these cells has been largely explored. Significant advances have been made in developing strategies that deliver, protect, and recruit stem cells, and the bioengineering field is evolving to improve current surgical techniques.
This review first describes current treatments and reports the recent progress in clinical investigations of stem and stromal cell-based therapies for musculoskeletal repair with a particular focus on bone and fibrocartilaginous tissues. The current understanding of appropriate cell sources and delivery strategies is then illustrated toward endogenous repair of musculoskeletal tissues. Last, emerging therapeutic concepts are highlighted in the context of biomaterials as a particularly attractive tool to control stem and stromal cell behavior both ex vivo and in vivo, to recruit endogenous stem cells, and to control the local healing environment. Such approaches have great potential for future therapies in musculoskeletal repair.
The intrinsic repair of bone defects mirrors many events of embryonic development and makes fracture healing one of the rare postnatal processes that are regenerative and can ultimately restore damaged tissue to its pre-injury structure, composition, and biomechanical function (Figure 1). In spite of the unique capacity of bone to heal, a number of clinical indications remain where therapeutic intervention is required. In the case of complex trauma with multiple fractures, infections, and tumor-associated and endocrine diseases (e.g., diabetes, osteoporosis), the body’s natural healing response is impaired, and non-union can occur in up to 15% of cases (Grayson et al., 2015). Another debilitating disorder is non-traumatic avascular osteonecrosis, which can lead to collapse of the femoral head and accounts for 10,000–20,000 total hip replacement surgeries in the United States per year (Figure 1; Moya-Angeler et al., 2015). Autologous bone grafting represents the gold standard for management of bone defects and non-unions, and union rates of more than 90% have been reported using iliac crest bone. However, considerable donor site morbidity and limited volumes must be taken into consideration. Additionally, allogeneic or synthetic bone substitutes, such as ceramics, corals, or polymer-based materials, have not reached the biological and mechanical properties equivalent to autologous bone (Table 1).
In addition to direct traumatic injury, complex damage of bone tissue (e.g., open fractures, tumor ablations) often results in concomitant soft tissue injury, including adjacent muscles. Although skeletal muscle has the inherent ability to regenerate after injuries, the regenerative capacity fails when a large volume of muscle is lost (i.e., volumetric loss). Such severe injuries may lead to fibrosis, atrophy, and ischemia when left untreated, accounting for significant socioeconomic costs ($18.5 billion in healthcare costs are associated with sarcopenia alone) (Janssen et al., 2004). Therapeutic treatment options are limited to physical therapy, scar tissue debridement, and transfer of healthy, innervated, and vascularized autologous muscle tissue. However, the outcomes of surgical reconstructions often remain aesthetically and functionally deficient (Grogan et al., 2011; Table 1).
Articular Cartilage and Meniscus
In contrast to bone and skeletal muscle tissue, the poor intrinsic healing capacity of articular cartilage and meniscus tissue presents a major challenge in clinics. Lesions from injuries or degeneration often result in gradual tissue erosion, leading to impaired function of the affected joint and degenerative osteoarthritis (OA) (Figure 1). Patients with post-traumatic OA account for more than 10% of the 27 million adults in the United States that have a clinical diagnosis of OA (Johnson and Hunter, 2014). Commonly, the first-line treatment of articular injuries includes arthroscopic lavage, partial meniscectomy, and BM stimulation techniques to penetrate subchondral bone (Table 1). Microfracture has been considered the gold standard for stimulating endogenous repair; however, it often results in the formation of inferior fibrocartilaginous repair tissue. This cartilaginous tissue is vulnerable due to altered biomechanics of the subchondral bone, which raises concerns about the long-term efficacy of microfracture (Solheim et al., 2016). Therefore, secondary and more complex procedures strive to restore the hyaline cartilage, such as osteochondral autografting from the less weight-bearing periphery (mosaicplasty) and autologous chondrocyte implantation (ACI). ACI represents one of the first clinical applications of tissue engineering where a biopsy from a low-weight-bearing region is performed, and ex vivo-expanded chondrocytes are implanted in a second operation. The de-differentiation of monolayer expanded chondrocytes and potential of recovery when implanted has been a matter of debate, and matrix-based ACI techniques have been developed that use absorbable scaffolds (e.g., porcine collagen) to support the implanted cells (Makris et al., 2015). An important limitation of these techniques is the long recovery time (6–12 months) to ensure neotissue formation. The choice of articular injury treatment depends on several factors, including localization and size of the lesion, the level of activity, and the degree of associated damage of menisci and ligaments.
Tears of the fibrocartilaginous menisci require surgical intervention for nearly 1 million patients in the United States annually (Vrancken et al., 2013). For lesions located in the peripheral vascularized region of the meniscus, repair strategies such as sutures and anchors allow preservation of the meniscal tissue. However, meniscal lesions often appear in the avascular central regions, which makes them less suitable for healing and usually requires partial or (sub)total meniscectomy (Figure 1; Table 1). In some cases, further treatment with a meniscal substitute, such as an allograft or a synthetic implant, is indicated to limit OA (Vrancken et al., 2013).
Other Fibrous Musculoskeletal Tissues
Another large proportion of musculoskeletal injuries in the clinic is represented by other damaged fibrous structures, including tendons, ligaments, and the annulus fibrosus (AF). Often, degenerative pathology precedes acute trauma, and, like articular cartilage, these tissues have a limited healing capacity. One of the most common tendon injuries presented clinically is tearing of one or more of the interdigitating tendons of the rotator cuff (Figure 1). Failure of initial physical therapy or acute trauma in young patients motivates surgical repair using open or arthroscopic approaches for subacromial decompression, tendon debridement, and suture or anchor supplementation (Table 1). Still, repair is limited, particularly within the complex anatomic arrangement forming the shoulder cuff. The formation of fibrovascular scar tissue frequently leads to significant morbidity, re-ruptures, and difficulties in treatment choice.
The intervertebral discs (IVDs) are composed of the nucleus pulposus (NP), a hydrophilic proteoglycan-rich gelatinous core, surrounded by a dense fibrocartilage ring—the AF (Figure 1). The gradual progression of IVD degeneration and the extrusion of the NP through defects in the AF is a major cause for lower back pain, a leading cause of global disability (Sakai and Andersson, 2015). Available treatments are mostly symptomatic, and surgical treatments often resect the structural obstruction resulting from herniation or fuse motion segments (Table 1). However, the complex structural features of IVDs surrounded by neural elements and inflammation frequently cause a homeostatic imbalance favoring a catabolic response governed by the loss of the IVD structure, which is often followed by facet joint arthritis and vertebra deformation, canal stenosis, and even deformations. Most importantly, disc replacement with synthetic implants or fusion of the motion segment does not cure the underlying pathology of IVD degeneration (Sakai and Andersson, 2015).
According to many physicians, PRP (Platelet-Rich Plasma) has been a lifesaver for their practice, while others claimed that it helped them become passionate about medicine again. This is because not only is it 100% from the body of the patient themselves, but it is also natural and comes with pretty much no side effects. It can also be used to treat a plethora of medical ailments, to the point where no other treatment options come close.
Although the above are all fantastic and solid reasons for offering PRP therapies, there are also a couple other reasons as well.
For instance, it is extremely simple compared to other treatment options. For about 1000$ as an initial investment, you can get started with offering PRP. The equipment is relatively cheap, and it pays for itself over a relatively short amount of time.
It also is not just a passing trend, as it has been going popular for a long time and shows no signs of slowing down. The market for PRP therapies is expected to reach almost 500 million dollars within the next 10 years, or an annual growth rate of 12.5% since 2015.
Patient satisfaction is another reason. In certain situations, the satisfaction rate for patients have been as high as 95%. This shocks many of the patients, who believe, although justifiably, that they cannot reverse or halt their condition without side effects, down time, and invasive surgeries.
The time for you to start including PRP into your practice is now, while the supply is low but the demand is booming. There is still a lot more promise when it comes to PRP as well, including combining PRP with other treatments to increase efficacy. Since no standard has yet to be established, you may be starting these standards yourself.
It is vital that we get more doctors to utilize PRP therapy so that they can be a pioneer in this field. PRP can turn medicine on its head, and missing out should not be a smart option.
The best part about it, is that PRP can be utilized in almost every field and specialty, from sports medicine, to pain management, skin rejuvenation, hair care, and even urology. Most of the physicians who utilize this treatment also saw higher patient retention rates as well.
So is there a legitimate reason to not add PRP to your practice?
Despite being rather simple, PRP extraction has been shrouded with debate on the reliability of the methods for the past decade. We are going to help clear up the debate by providing information on choosing the best PRP kit.
Using a kit is in itself vital to the creation of PRP. While it is possible to draw blood into a test tube and put it through a centrifuge and claim it is PRP, it’s otherwise ineffective. This is what is known as “bloody PRP,” and it might hold 1.5x the amount of blood platelets if you’re lucky, but it will also contain a ton of red and white blood cells. Because of this, this ineffective form of PRP can potentially cause flare ups after injection.
However, if you use a kit, that concentration of platelets can be as high as 5-7 times the baseline.
What Makes A PRP Kit Good?
This concentration of 5-7 times is vital for PRP to work, and kits allow you to choose whether or not you want to keep in the red and white blood cells, or whether you don’t. Each one would work on different ailments. However, some commercial kits may not deliver what you may want in your PRP, so it is good to know the difference between the kits.
- Gel Separators
Gel separators is pretty much just a test tube with some gel on the bottom. This gel is able to separate the blood from the platelets due to osmosis. The main issue is that when the test tube goes through the centrifuge, most of the platelets will also be caught by the gel as well. This will wind up with 1.5 times concentration of platelets at most, but it does take out the white and red blood cells as well, so that’s a plus.
- Buffy Coat
The kits that allow you to see a buffy coat are most likely to give you concentrations of 5-7 times. A buffy coat is a thin layer that is formed between the blood and the plasma after being in a centrifuge. This is mainly just platelets and white blood cells, with plasma on top, and packed blood underneath.
After this, you have to be able to separate the bufy coat from the red blood cells without contamination. This will help you to get PRP with less than 10% red blood cells.
- Buffy Coat with a Double Spin
The third and final type utilize a buffy coat which is devoid of red blood cells. This is the best kit on the market, because what you do is after separating the PRP from the red blood cells, you spin it again to further get rid of the red blood cells and to concentrate the platelets even more. After this, all that is needed to do is to separate the buffy coat, and this is PRP.
The Biosafe Kit
Although there are many kits that create PRP, the Biosafe kit has to be the best on the market. This is because it give you full control over the end product. Using this machine, you wind up with 10cc of usable product, which you can then double spin for that 5-7 times concentration. You can also choose whether or not you want some red blood cells in the finished product as well.
What is Leukocyte-poor PRP?
Leukocytes are otherwise known as White Blood Cells, and some researchers believe that they can be detrimental to PRP therapy. While there is no consensus as of yet, it is believed by many that these blood cells may trigger an inflammatory response, and even prevent growth factors from creating new cells.
However, some researchers believe that white blood cells are vital to a beneficial response. They believe that without these cells, you will be left with a lot of scar tissue at the site of healing. This Leukocyte-rich PRP also tends to have much more growth factors as well.
If you want to try leukocyte-poor PRP, you will need a Leukocyte Reduction filter, also known as an LR filter. These filters use electrostatic attraction to separate the white blood cells from the rest of the PRP. Although some filters can get clogged, a CIF-LR filter will be able to prevent that and filter out 99.99% of white blood cells.
There Is Plenty Of Evidence To Back This Up
Many people are highly skeptical about PRP, and are willing to ignore it without tons of randomized double-blind studies. Ignoring that some of the things that they do in their practice is also not proven in this manner. Many refuse to even look at the evidence, including the long line of evidence since the 1970’s, ranging over 6000 scientific studies.
The best evidence is how much clients will pay for this despite not being covered by insurance. This shows without any doubt that something about this treatment must be working. As long as there are clients, Adimarket will be there to provide the equipment for practices.
Although the clinical demand for bioengineered blood vessels continues to rise, current options for vascular conduits remain limited. The synergistic combination of emerging advances in tissue fabrication and stem cell engineering promises new strategies for engineering autologous blood vessels that recapitulate not only the mechanical properties of native vessels but also their biological function. Here we explore recent bioengineering advances in creating functional blood macro and microvessels, particularly featuring stem cells as a seed source. We also highlight progress in integrating engineered vascular tissues with the host after implantation as well as the exciting pre-clinical and clinical applications of this technology.
Ischemic diseases, such as atherosclerotic cardiovascular disease (CVD), remain one of the leading causes of mortality and morbidity across the world (GBD 2015 Mortality and Causes of Death Collaborators, 2016, Mozaffarian et al., 2016). These diseases have resulted in an ever-persistent demand for vascular conduits to reconstruct or bypass vascular occlusions and aneurysms. Synthetic grafts for replacing occluded arterial vessels were first introduced in the 1950s following surgical complications associated with harvesting vessels, the frequent shortage of allogeneic grafts, and immunologic rejection of large animal-derived vessels. However, despite advances in pharmacology, materials science, and device fabrication, these synthetic vascular grafts have not significantly decreased the overall mortality and morbidity (Nugent and Edelman, 2003, Prabhakaran et al., 2017). Synthetic grafts continue to exhibit a number of shortcomings that have limited their impact. These shortcomings include low patency rates for small diameter vessels (< 6 mm in diameter), a lack of growth potential for the pediatric population necessitating repeated interventions, and the susceptibility to infection. In addition to grafting, vascular conduits are also needed for clinical situations such as hemodialysis, which involves large volumes of blood that must be withdrawn and circulated back into a patient several times a week for several hours.
In addition to large-scale vessel complications, ischemic diseases also arise at the microvasculature level (< 1 mm in diameter), where replacing upstream arteries would not address the reperfusion needs of downstream tissues (Hausenloy and Yellon, 2013, Krug et al., 1966). Microvascularization has proven to be a critical step during regeneration and wound healing, where the delay of wound perfusion (in diabetic patients, for example) significantly slows down the formation of the granulation tissue and can lead to severe infection and ulceration (Baltzis et al., 2014, Brem and Tomic-Canic, 2007, Randeria et al., 2015).
In order to design advanced grafts, it is important to take structural components of a blood vessel into consideration, as understanding these elements is required for rational biomaterial design and choosing an appropriate cell source. Many of the different blood vessel beds also share some common structural features. Arteries, veins, and capillaries have a tunica intima comprised of endothelial cells (EC), which regulate coagulation, confer selective permeability, and participate in immune cell trafficking (Herbert and Stainier, 2011, Potente et al., 2011). Arteries and veins are further bound by a second layer, the tunica media, which is composed of smooth muscle cells (SMC), collagen, elastin, and proteoglycans, conferring strength to the vessel and acting as effectors of vascular tone. Arterioles and venules, which are smaller caliber equivalents of arteries and veins, are comprised of only a few layers of SMCs, while capillaries, which are the smallest vessels in size, have pericytes abutting the single layer of ECs and basement membrane. Vascular tissue engineering has evolved to generate constructs that incorporate the functionality of these structural layers, withstand physiologic stresses inherent to the cardiovascular system, and promote integration in host tissue without mounting immunologic rejection (Chang and Niklason, 2017).
A suitable cell source is also critical to help impart structural stability and facilitate in vivo integration. Patient-derived autologous cells are one potential cell source that has garnered interest because of their potential to minimize graft rejection. However, isolating and expanding viable primary cells to a therapeutically relevant scale may be limited given that patients with advanced arterial disease likely have cells with reduced growth or regenerative potential. With the advancement of stem cell (SC) technology and gene editing tools such as CRISPR, autologous adult and induced pluripotent stem cells (iPSCs) are emerging as promising alternative sources of ECs and perivascular SMCs that can be incorporated into the engineered vasculature (Chan et al., 2017, Wang et al., 2017).
Importantly, a viable cell source alone is not sufficient for therapeutic efficacy. Although vascular cells can contribute paracrine factors and have regenerative capacity, merely delivering a dispersed mixture of ECs to the host tissue has shown limited success at forming vasculature or integrating with the host vasculature (Chen et al., 2010). Therefore, recent tissue engineering efforts have instead focused on recreating the architecture and the function of the vasculature in vitro before implantation, with the hypothesis that pre-vascularized grafts and tissues enhance integration with the host. In this review, we explore recent advances in fabricating blood vessels of various calibers, from individual arterial vessels to vascular beds comprised of microvessels, and how these efforts facilitate the integration of the implanted vasculature within a host. We also discuss the extent to which SC-derived ECs and SMCs have been incorporated into these engineered tissues.
The first reported successful clinical application of TEBV in patients was performed by Shin’oka et al., who implanted a biodegradable construct as a pulmonary conduit in a child with pulmonary atresia and single ventricle anatomy (Shin’oka et al., 2001). The construct was composed of a synthetic polymer mixture of L-lactide and e-caprolactone, and it was reinforced with PGA and seeded with autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). The authors demonstrated patency and patient survival 7 months post-implant, and expanded their study to a series of 23 implanted TEBVs and 19 tissue patch repairs in pediatric patients (Hibino et al., 2010). They were noted to have no graft-related mortality, and four patients required interventions to relieve stenosis at a mean follow-up of 5.8 years. The first sheet-based technology to seed cultured autologous cells, developed by L’Heureux et al., was iterated by the group to induce cultured fibroblast cell sheet over a 10-week maturation period and produce tubules of endogenous ECM over a production time ranging between 6 and 9 months. They dehydrated and provided a living adventitial layer before seeding the constructs with ECs (L’Heureux et al., 2006). Their TEBV, named the Lifeline graft, was implanted in 9 of 10 enrolled patients with end-stage renal disease on hemodialysis and failing access grafts in a clinical trial. Six of the nine surviving patients had patent grafts at 6 months, while the remaining grafts failed due to thrombosis, rejection, and failure (McAllister et al., 2009). An attempt to create an “off the shelf” version of this graft in which pre-fabricated, frozen scaffolds were seeded with autologous endothelium prior to implantation led to 2 of the 3 implanted grafts failing due to stenosis, and one patient passed away due to graft infection (Benrashid et al., 2016).
Most recently, results were reported for the phase II trial of the decellularized engineered vessel Humacyte in end-stage renal disease patients surgically unsuitable for arterio-venous fistula creation (Lawson et al., 2016). This clinical scenario offers a relatively captive patient population in which graft complications are unlikely to be limb or life-threatening, and infectious and thrombotic event rates for traditional materials such as ePTFE are high (Haskal et al., 2010). The manufacturers seeded a 6mm PGA scaffold with SMCs from deceased organ and tissue donors and decellularized the scaffold following ECM production in an incubator coupled with a pulsatile pump prior to implantation. Humacyte demonstrated 63% primary patency at 6 months, 28% at 12 months, and 18% at 18 months post-implant in 60 patients. Ten grafts were abandoned. However, 12-month patency and mean procedure rate of 1.89 per patient-year to restore patency were comparable to PTFE grafts, while higher secondary patency rates were observed (89% versus 55%–65% at 1 year) (Huber et al., 2003, Lok et al., 2013). Although Humacyte revealed no immune sensitization and a lower infection rate than PTFEs (reported up to 12%) (Akoh and Patel, 2010), there remains much work to be done to improve primary patency and reduce the need for interventions.
Harnessing the regenerative functions reported in ECs derived from adult stem cells and iPSCs offers the promise of improving TEBV patency. Mcllhenny et al. generated ECs from adipose-derived stromal cells, transfected them with adenoviral vector carrying the endothelial nitric oxide synthase (eNOS) gene, and seeded the ECs onto decellularized human saphenous vein scaffolds (McIlhenny et al., 2015). They hypothesized that through inhibition of platelet aggregation and adhesion molecule expression, nitric oxide synthesis would prevent thrombotic occlusion in TEBV. Indeed, they reported patency with a non-thrombogenic surface 2 months post-implantation in rabbit aortas. While introducing additional complexities, engineering ECs and SMCs with other regenerative, anti-inflammatory, anti-thrombotic genes could perhaps bridge the functional difference between SC-derived cells and native primary cells.