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.

Bone 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).

Skeletal Muscle

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).

When it comes to side effects, ease of preparation, fast treatment times, and cost, PRP is above them all in orthobiologics. However, aside from PRP, there is one other alternative that is showing promise: Amniotic Fluid.
 
Due to it being a really good source of regenerative material that is not only highly proliferative, but also that produces almost no immune response, Amniotic Fluid has been a popular substance to theorize about since the late 1930’s. That is not all though, as this fluid is also high in collagen, growth factors, and hyaluronic acids. These are found in high quantities, making them a good choice for promoting regeneration.
 
This fluid is also high in stem cells that contain B7H4, a substance that promotes wound healing and even shows promise as a way of growing functional blood vessels. This was demonstrated to be true by scientists at Rice University and Texas Children’s Hospital.
 
However, we are not going to talk about that kind of Amniotic fluid. The one that we are going to talk about has been frozen, thereby killing the stem cells. This is actually a good thing, as the FDA has banned the presence of stems cells in amniotic fluids.
 
How Allografts Of Amniotic Fluids are Created
 
Allografts (Grafts taken from someone besides the person receiving it) of Amniotic Fluids are like Platelet-Rich Plasma that is already ready to be injected. This way, you and your patients receive all of the benefits associated with PRP therapy, without having to extract it yourself.
 
This amniotic fluid is taken with consent from mothers who decided to donate this fluid during a c-section. Not only were the women themselves pre-screened, but the fluid is tested again afterwards, and then prepared to be instantly used for a wide watch of medical ailments.
 
The fact that Amniotic Fluid has very little effect on one’s immune system makes it a wonderful allograft. This means that the body is far less likely to attack the donor material, making it far less likely to be rejected. Also, much like PRP, they are also known to fight inflammation, and keep microbes at bay. They are also multipotent cells, meaning they can turn into any cell they need to, making them a gold standard for regenerative medicine.
 
Since Amniotic Fluid is not taken from the person it it being used on like PRP, it misses out on a lot of those benefits. However, the large amount of elastin, fibronectin, and collagen makes it a great substance to use in wound healing and cell regeneration. It also contains a ton of growth factors, including PDGF, EGF, VEGF, and FDF to name a few.
 
Amniotic Fluid Allograft
 
It is often used to improve chronic pain conditions, as well as sports injuries, arthritis, and potentially even the symptoms of aging. It can be used by doctors along with PRP therapy to increase the effectiveness of the therapy. It can also be combined with bone marrow aspirates or hyaluronic acid.
 
The Potentials Of This
 
Many doctors may not want to spend the time and money investing in PRP therapies, so we think that Amniotic Fluid in general, could be a wonderful alternative to PRP therapy. Also, this can also be used as a stepping stone to help providers that are new to regenerative medicine to potentially get to PRP or stem cells over time.
 
We are convinced that once you get started with regenerative medicine, whether it be Amniotic Fluids, PRP therapies, or stem cell therapy, you will prefer it over other invasive procedures for sports injuries, arthritis, and other wounds. This will help save at least a few patients from having to do any unnecessary surgical procedures.

Although they can perform surgeries, osteopathic physicians try to avoid doing so whenever possible. Because of this, PRP seems to be an excellent fit for their practice. Since Osteopathy was built on the idea of self-healing, PRP seems to be a perfect fit.
 
A little while ago, PRP research was reviewed by The Journal Of The American Osteopathic Association, and concluded that more studies and evidence would be needed to make a solid statement on it. A little while later, a case study was filed, showcasing an 18 year old high school football player who suffered from a sports injury. The case study showed that the muscle injury healed rapidly under the effect of PRP therapy. So although PRP is not constantly held up on a pedestal by the mainstream yet, does not mean that Osteopathic Physicians can’t learn a lot or benefit from the use of PRP in their practice.
 
How Osteopathic Physicians can Benefit From PRP
 

1. It’s Holistic

 
Due to the fact that Osteopathic Physicians prefer to treat the patient, as opposed to just treating a disease or the symptoms, PRP is a great fit. It works by using the body’s own resources and mechanics and helps the body to heal itself over time. It works because, instead of simply dealing with symptoms, like many practices and conventional medicine does, it works to deal with the problem head on.
 
For instance, there are many examples of PRP therapy taking the place of surgery and medicine. Such as the cases where female patients were able to revive their sex drive, although they were initially treated for incontinence. So although PRP therapy was created and pushed by allopathic doctors at first, PRP works wonders in the field of Osteopathic medicine, and can become one of the best methods of treatment for Osteopathic physicians.
 

2. Musculoskeletal Issues

 
In some practices, musculoskeletal pain can be something that Osteopathic Physicians deal with often. However, it is good to note that PRP is quickly becoming one of the main treatments for these kinds of issues. For instance, many researchers believe that PRP should be the main choice for people who suffer from knee meniscus.
 
In 2016, University of Missouri Doctor Patrick Smith published a FDA-sanctioned double-blind randomized placebo controlled clinical trial on PRP. These kinds of trials are considered the gold standard in research. The results of the study was that PRP provided safe and notable benefits for people who suffer from knee Osteoarthritis.
 

3. PRP has a great deal of potential

 
The third and most important reason why all physicians, including Osteopathic Physicians, should start using PRP therapy is due to how wide its scope is. Due to the fact that PRP is simple and common, it is safe to say that if PRP can work on knee joints and tendons, that it most likely works on other tendons, joints, bones, and muscles as well. PRP will soon be a commonplace treatment when it comes to pretty much all musculoskeletal diseases.
 
This means that PRP has a near limitless potential. This is especially important for Osteopathic Physicians, as if there is a problem with the patients wrist, it could be that the main issue appears further down the arm. This is why multiple PRP injections on various areas of the arm can work to not just heal the issue, but also enhance the other traditional methods that are used. This will help restore the balance t the body, and give full functionality back to the patient.
 
American Academy of Regenerative Medicine Doctor Peter Lewis has administered over 100,000 PRP injections to over 12,000 patients. He claims that more than 80% of his patients who have gotten PRP therapy has had fantastic results. Even people who have claimed to need surgery could be benefited by the use of PRP.
 
Are They FDA Approved?
 
As of this year, PRP treatments are not yet subject to FDA approval. This is because all of the treatments are performed on the same day as the extraction, and uses only materials that are already inside the patients own body. Because of this, the PRP therapy is within the scope of the FDA Code of Federal Regulation title 21, part 1270, 1271.1. As a result, it is exempt from needing approval.

How does the U.S. FDA regulate cell therapies? (351 vs 361 Products)
In the United States, cellular therapies are regulated by the FDA’s Office of Cellular, Tissue, and Gene Therapies (OCTGT) within the FDA Center for Biologics Evaluation and Research (CBER).
According to the FDA, the Center for Biologics Evaluation and Research (CBER) regulates: